Nicotine salts, co-crystals, and salt co-crystal complexes

ABSTRACT

The invention provides certain nicotine salts, co-crystals, and salt co-crystals and provides novel polymorphic forms of certain nicotine salts. In particular, nicotine salts with orotic acid are described. The invention further provides methods of preparation and characterization of such nicotine salts. In addition, tobacco products, including smoking articles, smokeless tobacco products, and electronic smoking articles comprising nicotine salts, co-crystals, and/or salt co-crystals are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 14/721,283, filed May 26, 2015, which claimspriority to U.S. Provisional Patent Application No. 62/003,295, filedMay 27, 2014, which are incorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to various salts, co-crystals, and saltco-crystals of nicotine and to compositions and products (e.g., tobaccoproducts) into which such salts, co-crystals, and salt co-crystals canbe incorporated.

BACKGROUND OF THE INVENTION

Cigarettes, cigars and pipes are popular smoking articles that employtobacco in various forms. Such smoking articles are used by heating orburning tobacco, and aerosol (e.g., smoke) is inhaled by the smoker.Electronic smoking articles are a further type of tobacco product, whichcomprise a reservoir and heating system for the delivery ofaerosolizable materials. Tobacco also may be enjoyed in a so-called“smokeless” form. Particularly popular smokeless tobacco products areemployed by inserting some form of processed tobacco ortobacco-containing formulation into the mouth of the user.

Various types of cigarette components, including tobacco types, tobaccoblends, top dressing and casing materials, blend packing densities andtypes of paper wrapping materials for tobacco rods, are set forth in theart. See, for example, the various representative types of cigarettecomponents, as well as the various cigarette designs, formats,configurations and characteristics, that are set forth in Johnson,Development of Cigarette Components to Meet Industry Needs, 52^(nd)T.S.R.C. (September 1998); U.S. Pat. No. 5,101,839 to Jakob et al.; U.S.Pat. No. 5,159,944 to Arzonico et al.; U.S. Pat. No. 5,220,930 to Gentryand U.S. Pat. No. 6,779,530 to Kraker; US Pat. App. Pub. Nos.2005/0016556 to Ashcraft et al.; 2005/0066986 to Nestor et al.;2005/0076929 to Fitzgerald et al.; 2006/0272655 to Thomas et al.;2007/0056600 to Coleman, III et al.; and 2007/0246055 to Oglesby, eachof which is incorporated herein by reference.

Exemplary smokeless tobacco formulations, ingredients, and processingmethodologies are set forth in U.S. Pat. No. 1,376,586 to Schwartz; U.S.Pat. No. 3,696,917 to Levi; U.S. Pat. No. 4,513,756 to Pittman et al.;U.S. Pat. No. 4,528,993 to Sensabaugh, Jr. et al.; U.S. Pat. No.4,624,269 to Story et al.; U.S. Pat. No. 4,991,599 to Tibbetts; U.S.Pat. No. 4,987,907 to Townsend; U.S. Pat. No. 5,092,352 to Sprinkle, IIIet al.; U.S. Pat. No. 5,387,416 to White et al.; U.S. Pat. No. 6,668,839to Williams; U.S. Pat. No. 6,834,654 to Williams; U.S. Pat. No.6,953,040 to Atchley et al.; U.S. Pat. No. 7,032,601 to Atchley et al.;and U.S. Pat. No. 7,694,686 to Atchley et al.; US Pat. Pub. Nos.2004/0020503 to Williams; 2005/0115580 to Quinter et al.; 2006/0191548to Strickland et al.; 2007/0062549 to Holton, Jr. et al.; 2007/0186941to Holton, Jr. et al.; 2007/0186942 to Strickland et al.; 2008/0029110to Dube et al.; 2008/0029116 to Robinson et al.; 2008/0173317 toRobinson et al.; 2008/0196730 to Engstrom et al.; 2008/0209586 toNeilsen et al.; 2008/0305216 to Crawford et al.; 2009/0065013 to Essenet al.; 2009/0293889 to Kumar et al.; 2010/0291245 to Gao et al. and2011/0139164 to Mua et al.; PCT WO 04/095959 to Arnarp et al. and WO2010/132444 A2 to Atchley; each of which is incorporated herein byreference. Exemplary smokeless tobacco products that have been marketedinclude those referred to as CAMEL Snus, CAMEL Orbs, CAMEL Strips andCAMEL Sticks by R. J. Reynolds Tobacco Company; GRIZZLY moist tobacco,KODIAK moist tobacco, LEVI GARRETT loose tobacco and TAYLOR'S PRIDEloose tobacco by American Snuff Company, LLC; KAYAK moist snuff andCHATTANOOGA CHEW chewing tobacco by Swisher International, Inc.; REDMANchewing tobacco by Pinkerton Tobacco Co. LP; COPENHAGEN moist tobacco,COPENHAGEN Pouches, SKOAL Bandits, SKOAL Pouches, RED SEAL long cut andREVEL Mint Tobacco Packs by U.S. Smokeless Tobacco Company; and MARLBOROSnus and Taboka by Philip Morris USA.

Many smoking devices have been proposed through the years asimprovements upon, or alternatives to, smoking products that requirecombusting tobacco for use. Many of those devices purportedly have beendesigned to provide the sensations associated with cigarette, cigar, orpipe smoking, but without delivering considerable quantities ofincomplete combustion and pyrolysis products that result from theburning of tobacco. To this end, there have been proposed numeroussmoking products, flavor generators, and medicinal inhalers that utilizeelectrical energy to vaporize or heat a volatile material, or attempt toprovide the sensations of cigarette, cigar, or pipe smoking withoutburning tobacco to a significant degree. See, for example, the variousalternative smoking articles, aerosol delivery devices and heatgenerating sources set forth in the background art described in U.S.Pat. No. 7,726,320 to Robinson et al., U U.S. Pat. Pub. No. 2013/0255702to Griffith Jr. et al., U.S. Pat. Pub. Nos. 2014/0000638 to Sebastian etal., 2014/0060554 to Collett et al., 2014/0060555 to Chang et al.,2014/0096781 to Sears et al., 2014/0096782 to Ampolini et al., and2015/0059780 to Davis et al., which are incorporated herein by referencein their entireties.

Certain of these types of smoking articles, smokeless tobacco products,and electronic smoking articles comprise a tobacco extract, which insome products may be purified such that the extract is comprisedprimarily of nicotine. However, tobacco extracts comprising a highpercentage of nicotine (including extracts comprising at least about90%, at least about 95%, and at least about 99% nicotine by weight) aretypically in oil form. As such, nicotine extracts can be difficult tohandle and incorporate into certain tobacco products.

It would be desirable to provide such nicotine-based extracts in a formthat is amenable to incorporation in tobacco products. It would furtherbe desirable to incorporate such extracts into an enjoyable form of atobacco product and to provide processes for preparing such forms ofnicotine-based extracts as well as for preparing various types ofcompositions and products incorporating such forms of nicotine-basedextracts.

SUMMARY OF THE INVENTION

The present invention provides various forms of nicotine that can beapplicable to a wide range of products, including tobacco products.Particularly, the present application describes nicotine salts,co-crystals, and salt co-crystals and the preparation of such nicotinesalts, co-crystals, and salt co-crystals. It also describes theincorporation of such nicotine salts, co-crystals, and/or saltco-crystals into various products including tobacco products (e.g.,smoking articles, smokeless tobacco products, and electronic smokingarticles) and pharmaceutical products.

In a first aspect of the invention is provided a salt of nicotine andorotic acid. In some embodiments, the salt is a bis-orotic acidsalt-co-crystal. The bis-orotic acid salt-co-crystal can, in certainembodiments, be in hemi-hydrate form. In some embodiments, the salt is amono-orotic acid salt.

Advantageously, in some embodiments, a given percentage of the salt orsalt-co-crystal is in crystalline form. For example, in variousembodiments at least about 50% of the salt or salt-co-crystal is incrystalline form. In other embodiments, at least about 80 or at leastabout 90% of the salt or salt-co-crystal is in crystalline form.

The orotate salts or salt-co-crystals can, in some embodiments, becharacterized as having particular peaks in X-ray powder diffractionpatterns obtained therefrom. For example, one salt can be characterizedby an X-ray powder diffraction pattern having peaks at one or more ofthe following 2-theta diffraction angles: 8.8, 13.4, 17.7, 26.5, and29.3. As another example, one salt can be characterized by an X-raypowder diffraction pattern having peaks at one or more of the following2-theta diffraction angles: 9.1, 14.7, 15.4, 17.3, 25.0, 25.4, and 27.0.

The invention also provides nicotine fumarate salts and certain formsthereof, and products incorporating such salts.

The nicotine salts, co-crystals, and salt co-crystals described in thepresent application are generally applicable for use in a range ofproducts including, but not limited to, smoking articles, electronicsmoking articles, smokeless tobacco products (e.g., lozenges and gums),pharmaceutical products, and the like. Accordingly, in another aspect ofthe invention is provided a product incorporating one or more nicotinesalts, co-crystals, and/or salt co-crystals as described herein. Invarious embodiments, electronic smoking articles, smokeless tobaccoproducts, and/or pharmaceutical products incorporating one or more ofthe salts, co-crystals, and/or salt co-crystal complexes disclosedherein are provided.

For example, in one aspect, the disclosure provides an electronicsmoking article comprising an inhalable substance medium containedwithin a cartridge body and a heating member positioned to provide heatto at least a portion of the inhalable substance medium, wherein theinhalable substance medium comprises nicotine fumarate or a salt orsalt-co-crystal of nicotine and orotic acid. The inhalable substancemedium can further comprise, for example, one or more of glycerin,water, and a flavorant. The amount of nicotine fumarate or salt orsalt-co-crystal of nicotine and orotic acid incorporated can vary and,in some embodiments, can be that amount sufficient to provide nicotinein an amount of about 0.01 mg to about 0.5 mg, about 0.05 mg to about0.3 mg, or about 0.1 mg to about 0.2 mg per puff on the article.

In another aspect, the disclosure provides a smokeless tobacco productcomprising nicotine fumarate or a salt or salt-co-crystal of nicotineand orotic acid. Exemplary smokeless tobacco products include, but arenot limited to, loose moist snuff (e.g., snus); loose dry snuff; chewingtobacco; pelletized tobacco pieces; extruded or formed tobacco strips,pieces, rods, cylinders or sticks; finely divided ground powders; finelydivided or milled agglomerates of powdered pieces and components;flake-like pieces; molded tobacco pieces; gums; rolls of tape-likefilms; readily water-dissolvable or water-dispersible films or strips;meltable compositions; lozenges; pastilles; and capsule-like materialspossessing an outer shell and an inner region.

In a further aspect, the disclosure provides a pharmaceutical productcomprising a nicotine salt or crystalline polymorphic form as describedherein (e.g., nicotine fumarate or a salt or salt-co-crystal of nicotineand orotic acid). Such products can be, for example, in a form selectedfrom the group consisting of a pill, tablet, lozenge, capsule, caplet,pouch, gum, inhaler, solution, and cream. One exemplary lozengeformulation comprises one or more of the nicotine salts or crystallinepolymorphic forms disclosed herein and at least about 50% by weightisomalt.

Additionally, in a still further aspect, the disclosure provides methodsof preparing certain nicotine salts, salt-co-crystals, and crystallinepolymorphic forms. For example, the disclosure provides methods ofpreparing nicotine orotate salts or salt-co-crystals. In one embodiment,the disclosure provides a method of preparing a salt or salt-co-crystalof nicotine and orotic acid, comprising combining nicotine and oroticacid to form a solid and isolating the solid. In certain embodiments,the combining comprises grinding the nicotine and orotic acid orcomprises mixing the nicotine and orotic acid in neat nicotine or in asolvent selected from the group consisting of water, MEK, IPA, ethylacetate and mixtures thereof, and wherein the solid is a mono-orotatesalt (which can be in hemihydrate form). In certain embodiments, thecombining comprises mixing the nicotine and orotic acid in THF, ethanol,or a mixture thereof, and wherein the solid is a bis-orotatesalt-co-crystal (which can be non-solvated).

BRIEF DESCRIPTION OF THE DRAWINGS

In order to provide an understanding of embodiments of the invention,reference is made to the appended drawings, which are not necessarilydrawn to scale, and in which reference numerals refer to components ofexemplary embodiments of the invention. The drawings are exemplary only,and should not be construed as limiting the invention.

FIG. 1 provides XRPD diffractograms of solid materials prepared fromnicotine and orotic acid by various methods;

FIG. 2 provides additional XRPD diffractograms of solid materialsprepared from nicotine and orotic acid by various methods;

FIG. 3 provides high resolution XRPD diffractograms of solid materialsprepared from nicotine and orotic acid by various methods;

FIG. 4 provides ¹H NMR spectra of solid materials prepared from nicotineand orotic acid by various methods;

FIG. 5 provides an overlay of thermogravimetric analysis (TGA) anddifferential scanning calorimetry (DSC) thermograms for a materialprepared from nicotine and orotic acid in THF;

FIG. 6 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid in ethanol (EtOH);

FIG. 7 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid in neat nicotine;

FIG. 8 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid in water;

FIG. 9 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid via grinding;

FIG. 10 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid in a mixture of propan-2-ol (IPA)and water (80/20, v/v);

FIG. 11 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid in ethyl acetate (EtOAc);

FIG. 12 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and orotic acid in methyl ethyl ketone (MEK);

FIG. 13 provides an overlay of FT-IR spectra of nicotine orotate saltsexhibiting XRPD Patterns 1 and 2 and orotic acid;

FIG. 14 provides XRPD diffractograms from materials prepared fromnicotine and orotic acid by various methods, evaluating static stabilityof the salts;

FIG. 15 provides XRPD diffractograms for scaled up material preparedfrom nicotine and orotic acid in THF (exhibiting XRPD Orotate Pattern 1,indicating a bis-orotate salt-co-crystal);

FIG. 16 provides a high-resolution XRPD reference diffractogram forscaled up material prepared from nicotine and orotic acid in THF(exhibiting XRPD Orotate Pattern 1);

FIG. 17 provides a ¹H NMR spectrum for scaled up material prepared fromnicotine and orotic acid in THF (exhibiting XRPD Orotate Pattern 1);

FIG. 18 provides an FTIR spectrum of a scaled up material prepared fromnicotine and orotic acid in THF (exhibiting XRPD Orotate Pattern 1);

FIGS. 19(A) and 19(B) are microscopy images for a scaled up materialprepared from nicotine and orotic acid in THF (exhibiting XRPD OrotatePattern 1);

FIGS. 20(A) and 20(B) are scanning electron microscopy (SEM) images forscaled up material prepared from nicotine and orotic acid in THF(exhibiting XRPD Orotate Pattern 1);

FIG. 21 provides an overlay of TGA and DSC thermograms for a scaled upmaterial prepared from nicotine and orotic acid in THF (exhibiting XRPDOrotate Pattern 1);

FIG. 22 provides XRPD diffractograms for a static stability test withscaled up material prepared from nicotine and orotic acid in THF(exhibiting XRPD Orotate Pattern 1);

FIG. 23 provides high resolution XRPD diffractograms for a scaled upmaterial prepared from nicotine and orotic acid in EtOAc, comparedagainst a reference Orotate Pattern 1 XRPD diffractogram and a referenceOrotate Pattern 2 XRPD diffractogram;

FIG. 24 provides a further high resolution XRPD reference diffractogramfor a scaled up material prepared from nicotine and orotic acid in EtOAc(exhibiting XRPD Pattern 2, indicating a mono-orotate hemi-hydratesalt);

FIG. 25 provides ¹H NMR spectra for a scaled up material prepared fromnicotine and orotic acid in EtOAc (exhibiting XRPD Orotate Pattern 2);

FIG. 26 provides an FT-IR spectrum of a scaled up material prepared fromnicotine and orotic acid in EtOAc (exhibiting XRPD Orotate Pattern 2);

FIGS. 27(A) and 27(B) are microscopy images of a scaled up materialprepared from nicotine and orotic acid in EtOAc (exhibiting XRPD OrotatePattern 2);

FIGS. 28(A) and 28(B) are SEM images for a scaled up material preparedfrom nicotine and orotic acid in EtOAc (exhibiting XRPD Orotate Pattern2);

FIG. 29 provides an overlay of TGA and DSC thermograms for a scaled upmaterial prepared from nicotine and orotic acid in EtOAc (exhibitingXRPD Orotate Pattern 2);

FIG. 30 is an XRPD diffractogram for a static stability test with ascaled up material prepared from nicotine and orotic acid in EtOAc(exhibiting XRPD Orotate Pattern 2);

FIG. 31 provides XRPD diffractograms of materials prepared from nicotineand fumaric acid by various methods;

FIG. 32 provides high resolution XRPD diffractograms of solid materialsrecovered from nicotine and fumaric acid by various methods;

FIG. 33 provides ¹H NMR spectra of materials prepared from nicotine andfumaric acid by various methods;

FIG. 34 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and fumaric acid in neat nicotine;

FIG. 35 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and fumaric acid by grinding;

FIG. 36 provides an overlay of TGA and DSC thermograms for a materialprepared from nicotine and fumaric acid in EtOAc;

FIG. 37 provides XRPD diffractograms for nicotine fumarate saltsobtained by grinding;

FIG. 38 provides ¹H NMR spectra for the fumarate salts obtained bygrinding;

FIG. 39 provides high resolution XRPD diffractograms for scaled upnicotine fumarate salt (prepared in THF);

FIGS. 40(A) and 40(B) are microscopy images of a scaled up materialprepared from nicotine and fumaric acid in THF;

FIGS. 41(A) and 41(B) are SEM images for a scaled up material preparedfrom nicotine and fumaric acid in THF;

FIG. 42 provides an overlay of TGA and DSC thermograms for a scaled upmaterial prepared from nicotine and fumaric acid in THF;

FIG. 43 is an exploded perspective view of a smoking article having theform of a cigarette, showing the smokable material, the wrappingmaterial components, and the filter element of the cigarette;

FIG. 44 is a cross-sectional view of a smokeless tobacco productembodiment, taken across the width of the product, showing an outerpouch filled with a smokeless tobacco composition of the invention; and

FIG. 45 is a cross-sectional view of an electronic smoking article,which can encompass a variety of combinations of components useful informing an electronic aerosol delivery device.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention now will be described more fully hereinafter. Thisinvention may, however, be embodied in many different forms and shouldnot be construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey the scope of the invention to thoseskilled in the art. As used in this specification and the claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Reference to “dry weight percent” or“dry weight basis” refers to weight on the basis of dry ingredients(i.e., all ingredients except water).

The present invention relates to nicotine salts, co-crystals, and saltco-crystals and methods of preparation thereof. It also relates toproducts (including tobacco products and pharmaceutical products) thatcomprise one or more nicotine salts, co-crystals, and/or saltco-crystals. In certain embodiments, nicotine provided in one or moresuch forms can advantageously be isolated in a physical form that is animprovement over neat nicotine, which is a hygroscopic, oily liquid. Forexample, in certain embodiments, nicotine salts, co-crystals, and/orsalt co-crystals as described herein can be in an easier to handle formthan neat nicotine (e.g., a solid or semi-solid form), can be providedin a higher purity form than neat nicotine, and/or can exhibit greaterthermodynamic, physical, and/or chemical stability (e.g., a higherresistance to oxidation, reduced risk of hydrate formation, and/or alonger shelf life) than neat nicotine. In some embodiments, nicotinesalts, co-crystals, and/or salt co-crystals can provide increasedstability in the presence of relevant excipients in the product intowhich the salt, co-crystal, and/or salt co-crystal will be incorporated,as compared to neat nicotine. In some embodiments, nicotine salts,co-crystals, and salt co-crystals can exhibit a significant degree ofwater-solubility, rendering them applicable for incorporation within awide range of compositions and products.

Nicotine itself can be isolated and/or treated such that it is in one oftwo enantiomeric forms or it may be provided in racemic form. Nicotineis naturally occurring in levorotatory, (L)-nicotine form (also known as(−)-nicotine or S-nicotine). In the salts, co-crystals, and saltco-crystals provided herein, the nicotine is generally in the form of(L)-nicotine, although this disclosure is not intended to preclude thepreparation and application of dextrorotatory ((D)-nicotine) salts,co-crystals, and salt co-crystals or racemic forms of nicotine in thedisclosed salts, co-crystals, and salt co-crystals. Accordingly,nicotine salts, co-crystals, and salt co-crystals can be in anenantiomerically highly pure form (i.e., (L)- or (D)-form) or in racemicform as described herein.

A “nicotine salt” is a form of nicotine characterized by the interactionbetween nicotine in ionic form and a coformer in ionic form (e.g., anacid) via the transfer of one or more protons from the coformer donor tothe nicotine acceptor. The structure of nicotine is such that itcomprises two nitrogen atoms that are capable of accepting protons froma coformer and, accordingly, it can be present in non-protonated,mono-protonated, and/or di-protonated form in a given sample.

Certain nicotine salts are presently known. For example, nicotinesulfate has been sold as a pesticide and nicotine bitartrate dihydrate(also known as nicotine hydrogen tartrate) is a commercially available,water-soluble nicotine salt. Various other salts have been studied,including a nicotine acetic acid salt (which forms a viscous oil) aswell as, for example, nicotine citrates and nicotine malates. See, forexample, the types of ingredients and techniques set forth in U.S. Pat.No. 2,033,909 to Cox et al. and Perfetti, Beitrage Tabakforschung Int.,12, 43-54 (1983). Additionally, certain salts of nicotine have beenavailable from sources such as Pfaltz and Bauer, Inc. and K&KLaboratories, Division of ICN Biochemicals, Inc. Exemplary knownnicotine salts include nicotine salts such as nicotine tartrate andnicotine bitartrate, nicotine chloride (e.g., nicotine hydrochloride andnicotine dihydrochloride), nicotine sulfate, nicotine perchlorate,nicotine ascorbate, nicotine fumarate, nicotine citrate, nicotinemalate, nicotine lactate, nicotine aspartate, nicotine salicylate,nicotine tosylate, nicotine succinate, nicotine pyruvate, and nicotinesalt hydrates (e.g., nicotine zinc chloride monohydrate). A nicotinesalt with levulinic acid is discussed in US Pat. App. Pub. No.2011/0268809 and Int. App. Pub. No. PCT/US2011/033928, both to Brinkleyet al., which are incorporated herein by reference. See also, forexample, U.S. Pat. No. 4,830,028 to Lawson et al. and U.S. Pat. No.5,031,646 to Lippiello et al. and Leonard, Ind. Eng. Chem. 48: 1331-1341(1956). However, certain previously disclosed nicotine salts of organicacids are not commonly crystalline and can exhibit a range ofstoichiometries, which may make them unsuitable for use in certainapplications.

A “nicotine co-crystal” is a form of nicotine comprising nicotine and atleast one other component (“coformer”), both in neutral form.Co-crystals are typically characterized by a crystalline structure,which is generally held together by freely reversible, non-covalentinteractions. Co-crystals are typically made up of nicotine and at leastone other component in a defined stoichiometric ratio. In someembodiments, co-crystals can encompass hydrates, solvates, andclathrates. Co-crystals can comprise nicotine in combination with anorganic and/or an inorganic component. Co-crystals can generally bedistinguished from salts by the absence of a proton transfer between thecomponents (i.e., the nicotine and the one or more coformers) in aco-crystal. According to the U.S. Food and Drug Administration'sGuidance for Industry (April 2013), a co-crystal is defined as a solidthat is a crystalline material composed of two or more molecules in thesame crystal lattice, where the components are in a neutral state andinteract via nonionic interactions. See U.S. Department of Health andHuman Services, Food and Drug Administration, Guidance for Industry:Regulatory Classification of Pharmaceutical Co-Crystals (April 2013),which is incorporated herein by reference.

A “nicotine salt co-crystal” is a type of hybrid structure with bothsalt and co-crystal characteristics. Typically, a nicotine moleculewithin a salt co-crystal is associated with at least two coformers(which may be the same or different), wherein one coformer is in ionicform (e.g., an acid) and transfers a proton to the nicotine molecule andwherein a second coformer does not transfer a proton to the nicotinemolecule.

The stoichiometry of the salts, co-crystals, and salt co-crystalsdescribed herein can vary. For example, in certain embodiments, wheretwo components (i.e., nicotine and one coformer) are present, thenicotine:coformer stoichiometry can range in certain embodiments fromabout 5:1 to about 1:5 nicotine:coformer. Where more than one coformeris used to form a nicotine salt, co-crystal, or salt co-crystal, theratios of the coformers with respect to both the nicotine and to oneanother can also vary. In preferable embodiments, a given sample of thesalts, co-crystals, and salt co-crystals provided according to thepresent disclosure exhibit substantially one single stoichiometry.

The salts, co-crystals, and salt co-crystals described herein can, insome embodiments, exist in various polymorphic and pseudopolymorphicforms. Polymorphism is the ability of a crystalline material to exist inmore than one form or crystal structure. Polymorphism can result, e.g.,from the existence of different crystal packing structures (packingpolymorphism) or from the existence of different conformers of the samemolecule (conformational polymorphism). Pseudopolymorphism is the resultof hydration or solvation of a material and is also referred to assolvomorphism.

The salts, co-crystals, and salt co-crystals of the present disclosurecan incorporate nicotine derived from some form of a plant of theNicotiana species (e.g., some form of tobacco). The nicotine can be, forexample, in the form of a highly purified tobacco extract. Variousmethods are known for the isolation and purification of nicotine fromtobacco (including, but not limited to, extraction from tobacco withwater; extraction from tobacco with organic solvents; steam distillationfrom tobacco; or pyrolytic degradation of tobacco and distillation ofnicotine therefrom). For exemplary extraction methods, see for example,U.S. Pat. Nos. 2,822,306 and 4,153,063 to Roselius et al. and US Pat.App. Pub. No. 2008/0302377 to Kauryzbaev et al., which are incorporatedherein by reference.

The selection of the plant from the Nicotiana species (from which suchextracts and other tobacco materials that can be combined with thesalts, co-crystals, and/or salt co-crystals described herein areobtained) can vary; and in particular, the types of tobacco or tobaccosmay vary. Tobaccos that can be employed include flue-cured or Virginia(e.g., K326), burley, sun-cured (e.g., Indian Kurnool and Orientaltobaccos, including Katerini, Prelip, Komotini, Xanthi and Yamboltobaccos), Maryland, dark, dark-fired, dark air cured (e.g., Passanda,Cubano, Jatin and Bezuki tobaccos), light air cured (e.g., NorthWisconsin and Galpao tobaccos), Indian air cured, Red Russian andRustica tobaccos, as well as various other rare or specialty tobaccos.Descriptions of various types of tobaccos, growing practices andharvesting practices are set forth in Tobacco Production, Chemistry andTechnology, Davis et al. (Eds.) (1999), which is incorporated herein byreference. Nicotiana species can be derived using genetic-modificationor crossbreeding techniques (e.g., tobacco plants can be geneticallyengineered or crossbred to increase or decrease production of or toother change certain components, characteristics or attributes).Additional information on types of Nicotiana species suitable for use inthe present invention can be found in US Pat. App. Pub. No. 2012/0192880to Dube et al., which is incorporated by reference herein. Tobaccoplants can be grown in greenhouses, growth chambers, or outdoors infields, or grown hydroponically.

The portion or portions of the plant of the Nicotiana species usedaccording to the present invention can vary. For example, virtually allof the plant (e.g., the whole plant) can be harvested, and employed assuch. Alternatively, various parts or pieces of the plant can beharvested or separated for further use after harvest. For example, theleaves, stem, stalk, roots, lamina, flowers, seed, and various portionsand combinations thereof, can be isolated for further use or treatment.The plant material of the invention may thus comprise an entire plant orany portion of a plant of the Nicotiana species. See, for example, theportions of tobacco plants set forth in US Pat. App. Pub. Nos.2011/0174323 to Coleman, III et al. and 2012/0192880 to Dube et al.,which are incorporated by reference herein.

The plant of the Nicotiana species can be employed in either an immatureor mature form, and can be used in either a green form or a cured form,as described in 2012/0192880 to Dube et al., which is incorporated byreference herein. The tobacco material can be subjected to varioustreatment processes such as, refrigeration, freezing, drying (e.g.,freeze-drying or spray-drying), irradiation, yellowing, heating, cooking(e.g., roasting, frying or boiling), fermentation, bleaching orotherwise subjected to storage or treatment for later use. Exemplaryprocessing techniques are described, for example, in US Pat. App. Pub.Nos. 2009/0025739 to Brinkley et al. and 2011/0174323 to Coleman, III etal., which are incorporated by reference herein. At least a portion ofthe plant of the Nicotiana species can be treated with enzymes and/orprobiotics before or after harvest, as discussed in US Pat. App. Pub.Nos. 2013/0269719 to Marshall et al. and 2014/0020694 to Moldoveanu,which are incorporated herein by reference.

A harvested portion or portions of the plant of the Nicotiana speciescan be physically processed. A portion or portions of the plant can beseparated into individual parts or pieces (e.g., roots can be removedfrom stalks, stems can be removed from stalks, leaves can be removedfrom stalks and/or stems, petals can be removed from the remainingportion of the flower). The harvested portion or portions of the plantcan be further subdivided into parts or pieces (e.g., shredded, cut,comminuted, pulverized, milled or ground into pieces or parts that canbe characterized as filler-type pieces, granules, particulates or finepowders). The harvested portion or portions of the plant can besubjected to external forces or pressure (e.g., by being pressed orsubjected to roll treatment). When carrying out such processingconditions, the harvested portion or portions of the plant can have amoisture content that approximates its natural moisture content (e.g.,its moisture content immediately upon harvest), a moisture contentachieved by adding moisture to the harvested portion or portions of theplant, or a moisture content that results from the drying of theharvested portion or portions of the plant. As such, harvested portionor portions of the plant can be used as such as components of tobaccoproducts, or processed further.

To provide a nicotine extract, the plant of the Nicotiana species orportions thereof is typically subjected to one or more types ofprocessing conditions. Typical separation processes can include one ormore process steps (e.g., solvent extraction using polar solvents,organic solvents, and/or supercritical fluids), chromatography,distillation, filtration, recrystallization, and/or solvent-solventpartitioning. Exemplary extraction and separation solvents or carriersinclude water, alcohols (e.g., methanol or ethanol), hydrocarbons (e.g.,heptane and hexane), halogenated hydrocarbons (e.g.,monofluorotrichloromethane (Freon 11), dichlorotrifluoroethane (Freon123), and the like), diethyl ether, methylene chloride, andsupercritical carbon dioxide. See, for example, the description ofisolated tobacco components and techniques for isolation in U.S. Pat.No. 4,967,771 to Fagg et al., US Pat. App. Pub. Nos. 2011/0174323 toColeman, III et al.; 2011/0259353 to Coleman, III et al.; 2012/0192880to Dube et al.; 2012/0192882 to Dube et al.; and 2012/0211016 to Byrd,Jr. et al., which are incorporated by reference herein.

Although the nicotine incorporated within the salts, co-crystals, andsalt co-crystals of the present disclosure are commonly derived fromsome form of a plant of the Nicotiana species as outlined above, thesource of the nicotine is not limited thereto. For example, in someembodiments, nicotine may be provided synthetically. In someembodiments, nicotine may be obtained from another source (e.g., anothertype of plant).

Nicotine is typically isolated (e.g., as described above) in neat(liquid) form. According to the present invention, nicotine is modifiedsuch that it is provided in other forms by incorporating the nicotine asa component of a salt, co-crystal, or salt co-crystal, e.g., in the formof an oil, solid, semi-solid, etc. In some embodiments, certain salts,co-crystals, and salt co-crystals are desirably provided in solid form,e.g., solid, crystalline form. Advantageously (although notnecessarily), coformers (including acids) that are combined withnicotine to form such nicotine salts, co-crystals, or salt co-crystalsare “GRAS” (Generally Regarded As Safe) according to the U.S. Food andDrug Administration. Furthermore, it is beneficial (although again, notnecessary) for the nicotine salts, co-crystals, and/or salt co-crystalsproduced thereby to also be GRAS.

In one embodiment, a salt or salt-co-crystal of nicotine and orotic acidis provided. The stoichiometry of the orotate salts and salt-co-crystalsprovided herein can vary. For example, in certain embodiments, anicotine orotate salt or salt-co-crystal is provided having astoichiometry of between about 1:2 nicotine:acid and about 1:1nicotine:acid (i.e., having at least about 1 equivalent of acid pernicotine).

In certain embodiments, the nicotine orotate salt or salt-co-crystalsdisclosed herein are provided in solid form and may be in crystallineand/or amorphous form. In one form, the nicotine orotate (believed to bea bis-orotate salt-co-crystal) can be described as exhibiting an XRPDpattern (referred to herein as “Orotate Pattern 1”) with peaks at one ormore of the following 2-theta angles: 8.8, 13.4, 17.7, 26.5, and 29.3.Although not intending to be limited by theory, the relative pKa valuesof nicotine and orotic acid suggest that only one of the orotic acidmolecules is likely to be deprotonated, marking this material as asalt/co-crystal hybrid. Full characterization data, including a table ofall relevant peaks in the x-ray diffraction pattern is provided inExample 1. See also FIGS. 14-21, providing the results of variousmethods of characterization of a scaled up sample of this (OrotatePattern 1/bis-orotate salt-co-crystal) material.

In another form, the nicotine orotate (believed to be a mono-orotatehemi-hydrate salt) can be described as exhibiting an XRPD pattern(referred to herein as “Orotate Pattern 2”) with peaks at one or more ofthe following 2-theta angles: 9.1, 14.7, 15.4, 17.3, 25.0, 25.4, and27.0. Full characterization data, including a table of all relevantpeaks in the x-ray diffraction pattern is provided in Example 1. Seealso FIGS. 22-30, providing the results of various methods ofcharacterization of a scaled up sample of this (Orotate Pattern2/mono-orotate hemihydrate salt) material. It is noted that a variabletemperature XRPD experiment conducted with this material showed aconversion of Orotate Pattern 2 to Pattern 1 on heating (liberatingwater and nicotine). A first endotherm seen in the DSC is the melt ofPattern 2, with the release of the water and an exotherm seen is there-crystallization of Pattern 1, with associated loss of nicotine(second weight loss in the TGA). No change was seen in the diffractogramor visually at 180-200° C.; as such, the cause of this endotherm in theDSC (but repeat DSC experiments showed that it is reproducible). Thefinal endotherm and associated weight loss is the dissociation of themono-salt and release of the remainder of the nicotine to leave oroticacid. See FIG. 29. This was confirmed by a ¹H NMR experiment with theresidue, which was consistent with orotic acid.

In certain embodiments, the specific form of nicotine orotate can beaffected by the solvent in which it is prepared. For example, a materialprepared in THF or EtOAc was found to produce a material exhibitingOrotate Pattern 1, whereas a material prepared in neat nicotine, water,IPA/water, EtOAc, or by grinding was found to produce a materialexhibiting Orotate Pattern 2. See FIGS. 1-3 for XRPD traces comparingsolid materials obtained through various solvent screen studies,described in greater detail in Example 1. FIG. 4 provides ¹H NMR spectracomparing the materials. FIGS. 5-12 provide overlays of TGA and DSCthermograms of materials obtained in various solvents. Orotate Patterns1 and 2 have a complex relationship; during crystallization studies,Pattern 1 was observed to precipitate initially and then convert toPattern 2 upon stirring at 5° C. or on addition of excess nicotine.

The stabilities of these two solid forms of nicotine orotate (exhibitingXRPD Orotate Pattern 1 and Orotate Pattern 2) are analyzed by XPRD indry form and after 1 week at 40° C./75% relative humidity, as shown inFIG. 14. This study (and others) demonstrate that the bis-orotatesalt-co-crystal is thermally stable (melting at 239° C.) and thebis-orotate salt-co-crystal was shown to only slightly hygroscopic inGVS experiments. However, longer exposure to high humidity (25° C./96%RH for 1 week) caused conversion to a runny material.

In another embodiment, a salt of nicotine and fumaric acid is provided.The stoichiometry of the fumarate salt provided herein can vary. Forexample, in certain embodiments, a nicotine orotate salt orsalt-co-crystal is provided having a stoichiometry of between about 1:2nicotine:acid and about 1:1 nicotine:acid (i.e., having at least about 1equivalent of acid per nicotine).

Again, varying the method by which the fumaric acid and nicotine arecombined (e.g., by combining in different solvents) can, in someembodiments, provide different forms. One particular form isolatedaccording to the present disclosure (exhibiting an XRPD pattern referredto herein as “Fumarate Pattern 1”) is a non-solvated mono-salt. See FIG.39. This form can be prepared, e.g., in THF or by grinding. Thisnicotine fumarate can, in some embodiments, be described as exhibitingan XRPD pattern with peaks at one or more of the following 2-thetaangles: 14.9, 18.4, 19.9, and 22.4. Full characterization data,including a table of all relevant peaks in the x-ray diffraction patternis provided in Example 2. In certain embodiments, this nicotine fumaratesalt form is prone to deliquescing at high humidity and may notre-crystallize when humidity is reduced. In other embodiments, ametastable polymorph of the mono-fumarate salt is provided. This formcan be prepared, e.g., in neat nicotine.

In another embodiment, a salt of nicotine and pyroglutamic acid isprovided, with further detail provided in Example 3. This material isbelieved to exhibit some degree of crystallinity.

One skilled in the art will understand that all diffraction pattern dataprovided herein should not be construed as absolute and, accordingly,the nicotine salts and salt co-crystals of the invention are not limitedto particles having XRPD patterns identical to those in the referencedfigures. Any nicotine salts, co-crystals, or salt co-crystals havingXRPD patterns substantially the same as those of the relevant figureswill be considered to fall within the scope of the invention. A personskilled in the art of X-ray powder diffraction is able to judge thesubstantial identity of X-ray powder diffraction patterns. Generally, ameasurement error of a diffraction angle in an X-ray powderdiffractogram is about 2-theta=0.5° or less (more suitably, about2-theta=0.2° or less) and such degree of a measurement error should betaken into account when considering the X-ray powder diffraction patternin the figures provided herewith and/or the peak values provided herein.In other words, the peaks in the figures and the peak values giventhroughout the specification can be viewed, in certain embodiments, asbeing +/−0.5° or +/−0.2°. See Fundamentals of Powder Diffraction andStructural Characterization, Pecharsky and Zavalij, Kluwer AcademicPublishers, 2003.

Other nicotine salts, co-crystals, and salt co-crystals are alsoencompassed by the present disclosure. For a list of pharmaceuticallyacceptable counter-ions, see Handbook of PharmaceuticalSalts—Properties, Selection, and Use, P. Heinrich Stahl, Camille G.Wermuth (Eds.) VHCA (Verlag Helvetica Chemica Acta-Zürich), Wiley-VCH(New York) 2002, which is incorporated herein by reference. For example,certain coformers useful for reaction with the nicotine, which mayresult in the formation of a salt, co-crystal, or salt co-crystalinclude, but are not limited to: acetic acid; adipic acid; ascorbicacid; capric (decanoic) acid; citric acid; D-glucuronic acid; D-gluconicacid; DL-lactic acid; L-lactic acid; galactaric (mucic) acid; hippuric(N-benzoylglycine) acid; hydrochloric acid; L-aspartic acid; L-glutamicacid; L-glutaric acid; glycerophosphoric acid; glycolic acid; lauricacid; DL-malic acid; L-malic acid; DL-tartaric acid; L-tartaric acid;palmitic acid; phosphoric acid; sebacic (1,8-octanedicarboxylic) acid;stearic (octadecanoic) acid; succinic acid; sulfuric acid; andthiocyanic acid (HS-CN). Other exemplary coformers for reaction with thenicotine, which may result in the formation of a salt, co-crystal, orsalt co-crystal include, but are not limited to, (+)-camphoric acid;1,5-naphthalenedisulfonic acid; 1-hydroxy-2-naphthoic (xinafoic) acid;2,5-dihydroxybenzoic (gentisic) acid; benzenesulfonic acid; benzoicacid; caprylic (octanoic) acid; cyclamic acid; ethanesulfonic acid;fumaric acid; D-glucoheptonic acid; 4-hydroxybenzoic acid; isobutyricacid; ketoglutaric (2-oxo-glutaric) acid; 2-ketobutyric acid;lactobionic acid; maleic acid; malonic acid; methanesulfonic acid;naphthalene-2-sulfonic acid; nicotinic acid; oleic (Z-octadecenoic)acid; orotic acid; oxalic acid; pamoic acid; pivalic acid; propionicacid; L-pyroglutamic acid; and p-toluenesulfonic acid.

Certain other types of coformers are generally associated withpharmacological effects and are not typically preferred for thepreparation of salts, co-crystals, and salt co-crystals. Althoughcomplexes of nicotine with such coformers may not be preferred, incertain specialized embodiments, they may be reacted with nicotine toform salts, co-crystals, and/or salt co-crystals. Such coformersinclude, but are not limited to, (1S)-camphor-10-sulfonic acid;4-acetamidobenzoic acid; 4-aminosalicylic acid,N-acetyl-4-aminosalicylic acid; caproic (hexanoic) acid; dichloroaceticacid; hydrobromic acid; DL-mandelic acid; L-mandelic acid; nitric acid;formic acid; salicylic acid; cinnamic (e.g., trans-cinnamic) acid; andundecylenic acid. Other exemplary coformers that may form salts,co-crystals, and/or salt co-crystals with nicotine include, but are notlimited to, isothionic acid; lauric (dodecanoic) acid; 2-hydroxybenzoicacid; trans-2-hexanoic acid; trimesic acid; and 5-nitroisophthalic acid.

Various other coformers can be used to provide nicotine in the form of asalt, co-crystal, or co-crystal salt. Exemplary co-formers include, butare not limited to, L-proline, tromethamine; urea, xylitol; caffeine;glycine/glycine anhydride; vanillin; methyl 4-hydroxybenzoate(methylparaben); succinamide; L-alanine; mannitol; L-phenylalanine;saccharin; propylparaben; N-methylglucamine; L-tyrosine; gentisic acid;sorbic acid; benzoic acid; L-methionine; maltol; L-lysine, tromethamine;nicotinamide; isonicotinamide; phenylalanine; benzoquinone;terephthalaldehyde; 2,4-dihydroxybenzoic acid; and 4-hydroxybenzoicacid.

Additional coformers include pyruvic acid, 1-hydroxy-2-naphthoic acid,4-aminobenzoic acid, 3,5-dihydroxybenzoic acid, 2,3-dihydroxybenzoicacid, 3,4-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, vanillicacid, ethyl vanillin, isonicotinic acid, gallic acid, menthol (e.g.,racemic menthol or (−)-menthol), paracetamol, aspirin, ibuprofen,naproxen, ketoprofen, flurbiprofen, glucose, serine, malic acid,acetamide, sulfacetamide, benzoic acid, 4-aminobenzoic acid, creatine,2-hydroxyethanesulfonic acid, clofibric acid, taurine (tauric acid),iproniazid, L-histadine, L-arginine, L-asparagine, glutamine,L-cysteine, alanine, valine, isoleucine, leucine, morpholine, threonine,and N-methylglucamine.

Certain exemplary coformers that can provide a nicotine salt,co-crystal, or co-crystal salt are sugar-based acids (i.e.,monosaccharides with a carboxyl group). Representative types of sugaracids include aldonic acids (e.g., glyceric acid, xylonic acid, gluconicacid, and ascorbic acid), ulosonic acids (e.g., neuraminic acid andketodeoxyoctulosonic acid), uronic acids (e.g., glucuronic acid,galacturonic acid, and iduronic acid), and aldaric acids (e.g., tartaricacid, meso-galactaric acid/mucic acid, and D-glucaric acid/saccharicacid). In one preferred embodiment, the coformer or coformers used toprovide a nicotine salt, co-crystal, or salt co-crystal according to thepresent disclosure is an aldaric acid, and in a particular preferredembodiment, the aldaric acid is mucic acid((2S,3R,4S,5R)-2,3,4,5-tetrahydroxyhexanedioic acid, also referred to asgalactaric or meso-galactaric acid).

Other exemplary coformers that can provide a nicotine co-crystal, salt,or co-crystal salt are polyfunctional aromatic acids. Polyfunctionalaromatic acids often comprise a substituted or unsubstituted phenylgroup as the aromatic component, but can alternatively comprise anotheraromatic moiety, e.g., pyridine, pyrazine, imidazole, pyrazole, oxazole,thiophene, naphthalene, anthracene, and phenanthrene. Substituents onthe optionally substituted aromatic acids may be any type of substituent, including, but not limited to, halo (e.g., Cl, F, Br, and I);alkyl, halogenated alkyl (e.g., CF₃, 2-Br-ethyl, CH₂F, CH₂Cl, CH₂CF₃, orCF₂CF₃); alkenyl, hydroxyl; amino; carboxylate; carboxamido; alkylamino;arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid;sulfate; phosphonic acid; phosphate; and phosphonate groups. Exemplarypolyfunctional aromatic acids can be, for example:

substituted and unsubstituted aromatic dicarboxylic acids (e.g.,1,2-benzenedicarboxylic acid (phthalic acid), 1,3-benzenedicarboxylicacid (isophthalic acid), 1,4-benzenedicarboxylic acid (terephthalicacid), 2-iodo-1,3-benzenedicarboxylic acid,2-hydroxy-1,4-benzenedicarboxylic acid, 2-nitro-1,4-benzenedicarboxylicacid, 3-fluoro-1,2-benzenedicarboxylic acid,3-amino-1,2-benzenedicarboxylic acid, 3-nitro-1,2-benzenedicarboxylicacid, 4-bromo-1,3-benzenedicarboxylic acid,4-hydroxy-1,3-benzenedicarboxylic acid, 4-amino-1,2-benzenedicarboxylicacid, 4-nitro-1,2-benzenedicarboxylic acid,4-sulfo-1,2-benzenedicarboxylic acid, 4-amino-1,3-benzenedicarboxylicacid, 5-bromo-1,3-benzenedicarboxylic acid,5-hydroxy-1,3-benzenedicarboxylic acid, 5-amino-1,3-benzenedicarboxylicacid, 5-nitro-1,3-benzenedicarboxylic acid,5-ethynyl-1,3-benzenedicarboxylic acid, 5-cyano-1,3-benzenedicarboxylicacid, 5-nitro-1,3-benzenedicarboxylic acid,2,5-hydroxy-1,4-benzenedicarboxylic acid, and2,3,5,6-tetrafluoro-1,4-benzenedicarboxylic acid;

substituted and unsubstituted hydroxybenzoic acids (e.g.,2-hydroxybenzoic acid (salicylic acid), 3-hydroxybenzoic acid,4-hydroxybenzoic acid, 2-methyl-4-hydroxybenzoic acid,3-tert-butyl-4-hydroxybenzoic acid, 4-ethoxy-2-hydroxybenzoic acid,3-chloro-5-hydroxybenzoic acid, 5-chloro-2-hydroxybenzoic acid,3-bromo-4-hydroxybenzoic acid, 3-bromo-5-hydroxybenzoic acid,4-bromo-2-hydroxybenzoic acid, 5-bromo-2-hydroxybenzoic acid,2-fluoro-5-hydroxybenzoic acid, 3-fluoro-4-hydroxybenzoic acid,3-fluoro-2-hydroxybenzoic acid, 3-fluoro-5-hydroxybenzoic acid,2-fluoro-6-hydroxybenzoic acid, 4-fluoro-3-hydroxybenzoic acid,2-fluoro-4-hydroxybenzoic acid, 5-fluoro-2-hydroxybenzoic acid,2-amino-3-hydroxybenzoic acid, 2-amino-5-hydroxybenzoic acid,3-amino-2-hydroxybenzoic acid, 3-amino-4-hydroxybenzoic acid,3-amino-5-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid,4-amino-3-hydroxybenzoic acid, 5-amino-2-hydroxybenzoic acid(mesalamine), 5-aminomethyl-2-hydroxybenzoic acid,4-formyl-3-hydroxybenzoic acid, 3-formyl-4-hydroxybenzoic acid,5-(acetylamino)-2-hydroxybenzoic acid), 4-nitro-2-hydroxybenzoic acid,3,5-diethyl-4-hydroxybenzoic acid, 3,5-di-tert-butyl-4-hydroxybenzoicacid, 3,5-diisopropyl-2-hydroxybenzoic acid,3,4-dimethoxy-4-hydroxybenzoic acid (syringic acid),3,5-dichloro-2-hydroxybenzoic acid, 3,5-dichloro-4-hydroxybenzoic acid,3,6-dichloro-2-hydroxybenzoic acid, 2,3-difluoro-4-hydroxybenzoic acid,3,4-difluoro-2-hydroxybenzoic acid, 3,5-dibromo-2-hydroxybenzoic acid,3,5-diodo-2-hydroxybenzoic acid, 4-amino-5-chloro-2-hydroxybenzoic acid,3,5-dinitro-2-hydroxybenzoic acid, 2,4,6-tribromo-2-hydroxybenzoic acid,2,3,5,6-tetrafluoro-4-hydroxybenzoic acid, and2,3,4,5-tetrafluoro-6-hydroxybenzoic acid);

substituted and unsubstituted dihydroxybenzoic acids (e.g.,2,3-dihydroxybenzoic acid (pyrocatechuic acid/hypogallic acid),2,4-dihydroxybenzoic acid (β-resorcylic acid), 2,5-dihydroxybenzoic acid(gentisic acid/hydroquinonecarboxylic acid), 2,6-dihydroxybenzoic acid(γ-resorcylic acid), 3,4-dihydroxybenzoic acid (protocatechuic acid),3,5-dihydroxybenzoic acid (α-resorcylic acid),4-hydroxy-3-methoxybenzoic acid (vanillic acid),6-methyl-2,4-dihdroxybenzoic acid (orsellenic acid),4-bromo-3,5-dihydroxybenzoic acid, 5-bromo-2,4-dihydroxybenzoic acid,5-bromo-3,4-dihydroxybenzoic acid, 6-carboxymethyl-2,3-dihydroxybenzoicacid, 3,5-dibromo-2,4-dihydroxybenzoic acid,3,5-dichloro-2,6-dihydroxybenzoic acid, and5-amino-3-chloro-2,4-dihydroxybenzoic acid); and

substituted and unsubstituted trihydroxybenzoic acids (e.g.,2,3,4-trihydroxybenzoic acid, 2,4,5-trihydroxybenzoic acid,2,4,6-trihydroxybenzoic acid (phloroglucinol carboxylic acid), and3,4,5-trihydroxybenzoic acid (gallic acid)).

substituted and unsubstituted aromatic tricarboxylic acids (e.g.,1,2,3-benzenetricarboxylic acid, 1,2,4-benzenetricarboxylic acid(trimellitic acid); and

substituted and unsubstituted aromatic tetracarboxylic acids (e.g.,1,2,3,4-benzenetetracarboxylic acid (mellophanic acid) and1,2,4,5-benzenetetracarboxylic acid (pyromellitic acid).

Other coformers useful in certain embodiments are flavor acids,including but not limited to, 3-hydroxy-2-oxopropionic acid;2-oxobutyric acid (2-ketobutyric acid), 3-methyl-2-oxobutanoic acid;3-methyl-2-oxopentanoic acid; 4-methyl-2-oxopentanoic acid; and2-oxopentanedioic acid. Additional coformers can have higher molecularweights, such as 2-oxo-3-phenylpropionic acid; 5-oxooctanoic acid; and5-oxodecanoic acid.

It is noted that certain coformers as described herein may contain oneor more chiral centers, which may be either of the (R) or (S)configuration, or which may comprise a mixture thereof. As a result,various diastereomeric nicotine salts, co-crystals and salt co-crystalsmay be provided according to the present disclosure. The inventionincludes such diastereomers, either individually, or admixed in anyproportions. Certain coformers as described herein may be geometricisomers, including but not limited to cis and trans isomers across adouble bond. The invention includes all nicotine salts, co-crystals, andsalt co-crystals prepared with such isomers, which may be provided inthe form of pure isomers or in admixture with other isomers.

The method(s) by which the nicotine salts, co-crystals, and saltco-crystals described herein can be produced can vary. In someembodiments, no solvent (or a minimal amount of solvent) is used toprepare the nicotine salts, co-crystals, and salt co-crystals. Althoughin so-called “solventless” methods, a solvent is commonly not used, itis noted that one or more solvents may optionally be added (typically ina small amount) to the mixture to facilitate the formation of a nicotinesalt, co-crystal, or salt co-crystal. In certain embodiments, thecomponents (i.e., the nicotine and the one or more coformers) arecombined in the absence of a solvent to form a slurry. Solids comprisingnicotine salts, co-crystals, and/or salt co-crystals may be isolatedtherefrom via common methods (e.g., filtration). The slurry may beoptionally heated such that the nicotine and one or more coformersinteract in melted form to produce a salt, co-crystal, or saltco-crystal. In certain embodiments, physical methods are used to combinethe components (i.e., the nicotine and the one or more coformers). Forexample, the nicotine and the coformer(s) can be ground togethermechanically (e.g., using a mortar and pestle, ball mill, or vibratorymill).

In certain embodiments, a combination of nicotine and a coformer in agiven solvent (or solvents) and evaporation of that solvent can providethe desired nicotine salt, co-crystal, or salt co-crystal. Typically, insuch methods, the nicotine and coformer are provided in stoichiometricamounts (i.e., no excess nicotine or coformer is added). In suchmethods, selection of solvent is important, as the solvent (or solvents)in which the reaction is conducted can impact the intermolecularinteractions. The evaporation of solvent can be done at a controlledrate (e.g., slowly) to encourage the preparation of a single nicotinesalt, co-crystal, or salt co-crystal crystal for characterization. Forexample, the evaporation of solvent may be effected over the course ofhours, days, weeks, or months.

In some embodiments, a combination of nicotine and a coformer in a givensolvent (or solvents) and addition of a non-solvent can provide thedesired nicotine salt, co-crystal, or salt co-crystal. Exemplarysolvents and non-solvents that can be used for the preparation ofnicotine salts, co-crystals, and salt co-crystals include, but are notlimited to, water, alcohols (e.g., methanol, ethanol, n-butanol,isopropanol), ethers (e.g., diethyl ether, petroleum ether), ethylacetate (EtOAc), acetone, tetrahydrofuran (THF), methylene chloride(DCM), chloroform, alkanes (e.g., pentane, hexane, heptane, octane,nonane, cyclohexane), benzene, toluene, 1,4-dioxane, and combinationsthereof. In some embodiments, nicotine salts, co-crystals, and saltco-crystals can be prepared in supercritical fluids.

In other embodiments, the desired nicotine salt, co-crystal, or saltco-crystal can be prepared by freeze drying and subsequent maturation ofa solution of nicotine and one or more coformers. For example, asolution may be prepared, frozen, and lyophilized to remove the solvent.A maturation solvent can then be added and the resulting solids can beobtained by common methods (e.g., filtration). Maturation solventsinclude, but are not limited, the types of solvents noted above.

The method of production of nicotine salts, co-crystals, and saltco-crystals as described herein may, in some embodiments, employ anexcess of the coformer component. In such embodiments, it canadvantageously be possible to purify the resulting salt, co-crystal, orsalt co-crystal by removing excess coformer therefrom (i.e., thatcoformer which is not part of the structure of the salt, co-crystal, orsalt co-crystal). Exemplary means for salt, co-crystal, or saltco-crystal formation that may, in certain embodiments, be applicable forthe preparation of the nicotine salts, co-crystals, and salt co-crystalsdescribed herein are disclosed, for example, in U.S. Pat. No. 8,513,236to Schultheiss et al.; U.S. Pat. No. 8,470,832 to George et al.; U.S.Pat. No. 8,466,280 to Grunenberg et al.; U.S. Pat. No. 8,415,507 toSchultheiss et al.; U.S. Pat. No. 8,350,085 to Childs; U.S. Pat. No.8,241,371 to Hanna et al.; U.S. Pat. No. 8,212,079 to Childs; U.S. Pat.No. 8,173,625 to Brittain et al; U.S. Pat. No. 8,163,790 to Childs; U.S.Pat. No. 8,197,592 to Imamura et al.; U.S. Pat. No. 8,058,437 to Baueret al.; U.S. Pat. No. 7,935,817 to Blazecka et al.; U.S. Pat. No.7,927,613 to Almarsson et al.; U.S. Pat. No. 7,452,555 to Childs; U.S.Pat. No. 7,008,742 to Molaire; U.S. Pat. App. Pub. Nos. 2013/0203806 toChorlton et al.; 2013/0072440 to Dokou et al.; 2013/0040970 to Cosgroveet al.; 2012/0258170 to Kruthiventi et al.; 2012/0028998 to Sansone etal.; 2012/0028930 to Kalofonos et al.; 2012/0022117 to Gruss et al.;2011/0257340 to Childs; 2011/0251426 to Hanna et al.; 2011/0236478 toDokou et al.; 2011/0152266 to Grunenberg et al.; 2010/0204204 toZaworotko et al; 2008/0280858 to Hanna et al., 2007/0287194 to Childs etal.; 2003/0224006 to Zaworotko et al.; and 2002/0048610 to Cima et al.,which are all incorporated herein by reference in their entireties.Other references that provide exemplary means for the formation ofcertain nicotine salts include M. Dezelic and B. Nikolin, “NicotineCompounds with Aromatic Acids. Part II.,” Glasnik Drustva HemicaraTechnol. N. R. Bosne I Hercegovine, Sarajevo, 10 (1961) 55-62 and M.Dezelic and D. Tomic, “Nicotine Compounds with Aromatic Acids,” Kem.Vjestnik 17 (1943):39-57, which are incorporated herein by reference.

For the preparation of the nicotine salts, co-crystals, andsalt-co-crystals disclosed herein, the product can, in some embodiments,be provided by combining an acid (e.g., orotic acid, fumaric acid, orpyroglutamic acid) and nicotine in the absence of solvent. In someembodiments, an excess of nicotine is added to the reaction mixture and,advantageously, excess nicotine is removed (e.g., by vacuum and/or bywashing/filtration, such as with THF, heptane, and/or EtOAc). Althoughsuch slurry methods commonly employ no solvent, it is noted that, insome embodiments, some solvent can be added to facilitate the formationof a salt, co-crystal, or salt-co-crystal.

In some embodiments, a solvent is used to facilitate salt formation. Forexample, an acid can be dissolved in THF, nicotine can be added thereto,and the resulting mixture can be stirred/shaken to produce the salt,co-crystal, or salt-co-crystal. Although a single solvent can, in someembodiments, be sufficient to form the desired salt, co-crystal, orsalt-co-crystal, in some embodiments, an anti-solvent is used to promotethe formation of a solid material. The solvent can be removed (e.g., byevaporation) to provide the salt, co-crystal, or salt-co-crystal. Insome embodiments, the solid is washed, e.g., with THF, heptane, and/orEtOAc. In some embodiments, mechanical grinding is used to promote theformation of the salt, co-crystal, or salt-co-crystal, as will bedescribed further herein (see, e.g., the Examples).

Desirably, single crystal x-ray diffraction (SCXRD) can be used in someembodiments to determine the makeup of the solids (i.e., the nicotinesalts, co-crystals, and salt co-crystals). However, suitable, x-rayquality crystals cannot always be readily produced. Therefore, a varietyof other solid state spectroscopic techniques can be used including, butnot limited to, x-ray powder diffraction (MOD), Raman spectroscopy, FTIRspectroscopy, vibrational spectroscopy, polarized light microscopy(PLM), and solid state NMR. The nicotine salts, co-crystals, and saltco-crystals described herein may be further characterized, for example,using such techniques as ¹³C NMR and ¹H NMR (in a suitable solvent,e.g., in D₂O or DMSO-d₆) to evaluate the chemical structure, GravimetricVapor Sorption (GVS) to evaluate the hygroscopicity, thermogravimetricanalysis (TGA) and differential scanning calorimetry (DSC) to evaluatethe thermal properties, and/or chromatography (e.g., HPLC) in a suitablesolvent to evaluate the purity. Products as described herein can befurther analyzed via Karl Fischer Titration (KF) to determine the watercontent.

It is noted that, in certain cases, it is difficult to distinguishbetween co-crystals and salts. Typically, distinguishing a salt from aco-crystal requires evidence of proton transfer, which may not bestraightforward to identify even with single crystal x-ray diffraction.In other terms, distinguishing a salt from a co-crystal generallyrequires evidence of ionic interactions, as opposed to merely non-ionicinteractions. Accordingly, although the novel compositions describedherein are described as salts, it is noted that in some embodiments, itmay not be known whether a given product exists in salt, co-crystal, orsalt co-crystal form or in some type of intermediate form (e.g., whereinthe proton has not been transferred to a basic site, but may reside inspace between the donor coformer and acceptor).

The nicotine salts, co-crystals, and salt co-crystals described hereincan be incorporated into various products, including tobacco-containingproducts. The important characteristics of nicotine salts, co-crystals,and salt co-crystals for use in different types of products vary, aswill be discussed in detail below.

The nicotine salts, co-crystals, and salt co-crystals provided hereincan, in some embodiments, be used as compositions in the manufacture ofsmoking articles. For example, salts, co-crystals, and salt co-crystalsprepared in accordance with the present invention can be mixed withcasing materials and applied to tobacco as a casing ingredient or as atop dressing. Still further, salts, co-crystals, and salt co-crystals ofthe present disclosure can be incorporated into a cigarette filter(e.g., in the filter plug, plug wrap, or tipping paper) or incorporatedinto cigarette wrapping paper, preferably on the inside surface, duringthe cigarette manufacturing process. See, for example, the descriptionand references related to tobacco isolates used in smoking articles setforth in US Pat. Pub. No. 2012/0192880 to Dube et al., which isincorporated by reference herein. Representative tobacco blends,non-tobacco components, and representative cigarettes manufacturedtherefrom are also set forth in the Dube et al. reference noted above.

Typically, the amount of nicotine salt, co-crystal, or salt co-crystalincorporated into a smoking article is that amount sufficient to providethe desired amount of free nicotine in the mainstream smoke producedtherefrom. For example, in some embodiments, the smoking article mayprovide nicotine in an amount of about 0.1 mg to about 10 mg, about 0.5mg to about 9 mg, or about 1 mg to about 8 mg. Accordingly, the amountof nicotine salt, co-crystal, or salt co-crystal incorporated into thesmoking article can be, for example, that amount sufficient to producethese amounts of nicotine when the article is used.

Referring to FIG. 43, there is shown a smoking article 10 in the form ofa cigarette and possessing certain representative components of asmoking article that can contain the formulation of the presentinvention. The cigarette 10 includes a generally cylindrical rod 12 of acharge or roll of smokable filler material (e.g., about 0.3 g to about1.0 g of smokable filler material such as tobacco material) contained ina circumscribing wrapping material 16. The rod 12 is conventionallyreferred to as a “tobacco rod.” The ends of the tobacco rod 12 are opento expose the smokable filler material. The cigarette 10 is shown ashaving one optional band 22 (e.g., a printed coating including afilm-forming agent, such as starch, ethylcellulose, or sodium alginate)applied to the wrapping material 16, and that band circumscribes thecigarette rod in a direction transverse to the longitudinal axis of thecigarette. The band 22 can be printed on the inner surface of thewrapping material (i.e., facing the smokable filler material), or lesspreferably, on the outer surface of the wrapping material.

At one end of the tobacco rod 12 is the lighting end 18, and at themouth end 20 is positioned a filter element 26. The filter element 26positioned adjacent one end of the tobacco rod 12 such that the filterelement and tobacco rod are axially aligned in an end-to-endrelationship, preferably abutting one another. Filter element 26 mayhave a generally cylindrical shape, and the diameter thereof may beessentially equal to the diameter of the tobacco rod. The ends of thefilter element 26 permit the passage of air and smoke therethrough.

A ventilated or air diluted smoking article can be provided with anoptional air dilution means, such as a series of perforations 30, eachof which extend through the tipping material and plug wrap. The optionalperforations 30 can be made by various techniques known to those ofordinary skill in the art, such as laser perforation techniques.Alternatively, so-called off-line air dilution techniques can be used(e.g., through the use of porous paper plug wrap and pre-perforatedtipping paper). The salts of the invention can be incorporated withinany of the components of a smoking article, including but not limitedto, as a component of the tobacco charge, as a component of the wrappingpaper (e.g., included within the paper or coated on the interior orexterior of the paper), as an adhesive, as a filter element component,and/or within a capsule located in any region of the smoking article.

The temperature at which nicotine, the coformer component (orcomponents), and any degradation products thereof are released from anicotine salt, co-crystal, or salt co-crystal can be a relevantconsideration in the context of smoking articles. It is typicallyimportant that nicotine is released from the salt, co-crystal, or saltco-crystal (i.e., that the nicotine transfers to the mainstream smokeand is delivered to the user) at the burn temperature of the smokingarticle. It can also be important in some embodiments to ensure thatcertain undesirable coformers and/or degradation products thereof arenot transferred to the mainstream smoke (and delivered to the user). Therelevant temperature may vary slightly, depending upon the specificlocation(s) of the salt, co-crystal, or salt co-crystal within thesmoking article. For example, in certain embodiments, the temperature atwhich a smoking article burns (and thus the temperature to which thesalt is exposed) can be between at least about 100° C., at least about200° C., or at least about 500° C., including between about 100° C. andabout 500° C. in certain regions of a smoking article and between about600° C. and about 900° C. in other regions of a smoking article. Theseconsiderations can impact selection of the salts, co-crystals, or saltco-crystals that are suitable for a particular application.

In other embodiments, the nicotine salts, co-crystals, and saltco-crystals disclosed herein can be incorporated within smokelesstobacco products. Representative smokeless tobacco compositionsaccording to the present invention can have various types of formats andconfigurations, and as a result, the character, nature, behavior,consistency, shape, form, size and weight of the composition can vary.In some embodiments, the nicotine salts, co-crystals, and saltco-crystals disclosed herein can be incorporated into smokeless tobaccoproducts, such as loose moist snuff (e.g., snus); loose dry snuff;chewing tobacco; pelletized tobacco pieces; extruded or formed tobaccostrips, pieces, rods, cylinders or sticks; finely divided groundpowders; finely divided or milled agglomerates of powdered pieces andcomponents; flake-like pieces; molded tobacco pieces; gums; rolls oftape-like films; readily water-dissolvable or water-dispersible films orstrips; meltable compositions; lozenges; pastilles; or capsule-likematerials possessing an outer shell and an inner region. The shape of arepresentative composition can be generally spherical, cylindrical(e.g., ranging from the general shape of a flattened disc to the generalshape of a relatively long, slender stick), helical, obloid, square,rectangular, or the like; or the composition can have the form of abead, granular powder, crystalline powder, capsule, film, strip, gel, orthe like. The shape of the composition can resemble a wide variety ofpill, tablet, lozenge, capsule, and caplet types of products. Varioustypes of smokeless tobacco products are described or referenced in USPat. Pub. Nos. 2013/0206150 to Duggins et al.; 2013/0074855 to Holton,Jr.; 2012/0118310 to Cantrell et al.; 2012/0138073 to Cantrell et al.;2012/0138074 to Cantrell et al.; and 2012/0152265 to Dube et al., whichare all incorporated herein by reference.

Referring to FIG. 44, a representative snus type of tobacco productcomprising one or more nicotine salts, co-crystals, or salt co-crystalsaccording to the present disclosure is shown. In particular, FIG. 44illustrates a smokeless tobacco product 40 having a water-permeableouter pouch 42 containing a smokeless tobacco composition 44. Any of thecomponents of the tobacco product can comprise one or more nicotinesalts, co-crystals, or salt co-crystals, according to the presentdisclosure (e.g., the interior or exterior of the pouch lining or aportion of the smokeless tobacco composition contained therein).

Other exemplary smokeless tobacco products into which the salts,co-crystals, and salt co-crystals described herein can be incorporatedcan have the form of a gum, lozenge, tablet, microtab, or othertablet-type product. See, for example, the types of nicotine-containinglozenges, lozenge formulations, lozenge formats and configurations,lozenge characteristics and techniques for formulating or manufacturinglozenges set forth in U.S. Pat. No. 4,967,773 to Shaw; U.S. Pat. No.5,110,605 to Acharya; U.S. Pat. No. 5,733,574 to Dam; U.S. Pat. No.6,280,761 to Santus; U.S. Pat. No. 6,676,959 to Andersson et al.; U.S.Pat. No. 6,248,760 to Wilhelmsen; and U.S. Pat. No. 7,374,779; US Pat.Pub. Nos. 2013/0074855 and 2013/0078307 to Holton, Jr.; 2001/0016593 toWilhelmsen; 2004/0101543 to Liu et al.; 2006/0120974 to Mcneight;2008/0020050 to Chau et al.; 2009/0081291 to Gin et al.; and2010/0004294 to Axelsson et al.; and 2013/0312774 to Holton, Jr., whichare all incorporated herein by reference.

One representative type of smokeless tobacco product comprising one ormore of the nicotine salts, co-crystals, or salt co-crystals describedherein is a lozenge, e.g., as substantially described in US Pat. App.Pub. Nos. 2013/0312774, 2013/0074856, and 2013/0074855, all to Holton,Jr., which are incorporated herein by reference. Such lozenges cancomprise, in addition to one or more nicotine salts, co-crystals, orsalt-co-crystals, a majority of one or more sugar alcohols (e.g.,isomalt and maltitol syrup), e.g., in an amount of at least about 50% byweight, at least about 70% by weight, at least about 80% by weight, orat least about 90% by weight. Other ingredients of particular interestin such lozenge products include, but are not limited to, salts (e.g.,NaCl), sweeteners (e.g., sucralose), and one or more flavorings.

The amount of nicotine salt, co-crystal, or salt co-crystal incorporatedwithin a smokeless tobacco composition can vary and can be dependent, inpart, on the specific type of smokeless tobacco composition. Clearly,the amount of a given nicotine salt, co-crystal, or salt co-crystal tobe incorporated within a product will depend on the desired nicotinecontent of that product, and can be calculated based on the mass of thecoformer and the stoichiometry of the salt, co-crystal, or saltco-crystal. Exemplary amounts include from about 0.1% by weight of theconsumable material to about 10% by weight of the consumable orinhalable material. For example, for a lozenge, the amount of nicotinesalt, co-crystal, or salt co-crystal is at least about 0.5%, generallyat least about 1%, often at least about 1.5%, often at least about 2%,often at least about 2.5%, and frequently at least about 3% by weight ofthe product, e.g., about 0.5% to about 10%, including about 1% to about5% by weight of the product. The amount of nicotine salt, co-crystal, orsalt co-crystal can be determined based on the desired nicotine contentin the lozenge.

Various other substances can be added to the smokeless tobaccocompositions comprising the nicotine salts, co-crystals, or saltco-crystals of the present invention. For example, excipients such asfillers or carriers for active ingredients (e.g., calcium polycarbophil,microcrystalline cellulose, hydroxypropylcellulose, sodiumcarboxymethylcellulose, cornstarch, silicon dioxide, calcium carbonate,lactose, and starches including potato starch, maize starch, etc.),thickeners, film formers and binders (e.g., hydroxypropyl cellulose,hydroxypropyl methylcellulose, acacia, sodium alginate, gum arabic,lecithin, xanthan gum and gelatin), antiadherents (e.g., talc), glidants(e.g., colloidal silica), humectants (e.g., glycerin), preservatives andantioxidants (e.g., sodium benzoate and ascorbyl palmitate), surfactants(e.g., polysorbate 80), dyes or pigments (e.g., titanium dioxide or D&CYellow No. 10), and lubricants or processing aids (e.g., calciumstearate or magnesium stearate) are added to the compositions in certainembodiments. Other exemplary types of ingredients include salts (e.g.,sodium chloride, potassium chloride, sodium citrate, potassium citrate,sodium acetate, potassium acetate, and the like), natural sweeteners(e.g., fructose, sucrose, glucose, maltose, vanillin, ethyl vanillinglucoside, mannose, galactose, lactose, and the like), artificialsweeteners (e.g., sucralose, saccharin, aspartame, acesulfame K, neotameand the like), pH adjusters or buffering agents (e.g., metal hydroxides,preferably alkali metal hydroxides such as sodium hydroxide andpotassium hydroxide, and other alkali metal buffers such as metalcarbonates, preferably potassium carbonate or sodium carbonate, or metalbicarbonates such as sodium bicarbonate, and the like), effervescingmaterials such as certain acid/base combinations, oral care additives(e.g., thyme oil, Eucalyptus oil, and zinc), preservatives (e.g.,potassium sorbate, and the like), syrups (e.g., honey, high fructosecorn syrup, and the like), and mixtures thereof. In certain embodiments,the smokeless tobacco composition can include lipid components thatprovide a meltable composition that melts (as opposed to merelydissolving) in the oral cavity, such as compositions set forth in USPat. Pub. No. 2012/0037175 to Cantrell et al., which is incorporated byreference herein. Exemplary encapsulated additives that can be includedwithin the smokeless tobacco products disclosed herein are described,for example, in WO 2010/132444 to Atchley, which has been previouslyincorporated by reference herein. See also, the smokeless tobaccoingredients set forth in US Pat. Pub. Nos. 2012/0055494 to Hunt et al.and 2012/0199145 to Byrd et al., which are incorporated by referenceherein.

The manners and methods used to formulate and manufacture the smokelesstobacco product can vary. Ingredients, including the nicotine salts,co-crystals, or salt co-crystals described herein, can be combined andprocessed into the desired composition by techniques such as extrusion,compression, molding, spraying, and the like. It is noted that certainconsiderations noted above for electronic smoking articles are notrelevant in the context of a smokeless tobacco product. For example,nicotine salts, co-crystals, or salt co-crystals that are useful insmokeless tobacco products need not transfer to aerosol form at a giventemperature. In smokeless tobacco products, the main consideration isthat the nicotine salt, co-crystal, or salt co-crystal contained thereincan provide nicotine when the smokeless tobacco product is placed in themouth of the user (i.e., at some point during residence of the smokelesstobacco product in the mouth of the user). Accordingly, certain nicotinesalts, co-crystals, or salt co-crystals that are useful for one type oftobacco product may not be useful for others.

In certain embodiments, the nicotine salts, co-crystals, and saltco-crystals provided according to the present disclosure areincorporated within electronic smoking articles. An exemplary embodimentof an electronic smoking article 200 incorporating a nicotine salt,co-crystal, or salt co-crystal according to the present disclosure isshown in FIG. 45. As illustrated therein, a control body 202 can beformed of a housing 201 that can include a control component 206, a flowsensor 208, a battery 210, and an LED 212. The electronic smokingarticle also may comprise a cartridge 204 that can be formed of ahousing 203 enclosing a reservoir 244 that is in fluid communicationwith a transport element 236 adapted to wick or otherwise transport anaerosol precursor composition stored in the reservoir to a heater 234(e.g., a resistive heating wire that may be coiled around at least aportion of the transport element). Exemplary reservoirs and transportelements are disclosed in US Pat. Pub. No. 2014/0261487 to Chapman etal., and exemplary heaters are disclosed in US Pat. Pub. No.2014/0157583 to Ward et al., the disclosures of which are incorporatedherein by reference in their entireties. An opening 228 may be presentin the cartridge housing 203 at a mouthend 205 thereof to allow foregress of formed aerosol from the cartridge 204. Such components arerepresentative of the components that may be present in a control bodyand/or cartridge and are not intended to limit the scope of componentsthat are encompassed by the present disclosure.

The cartridge 204 may be adapted to engage the control body 202 througha press-fit engagement between the control body projection 224 and thecartridge receptacle 240. Such engagement can facilitate a stableconnection between the control body 202 and the cartridge 204 as well asestablish an electrical connection between the battery 210 and controlcomponent 206 in the control body and the heater 234 in the cartridge.Other types of connections (e.g., a screw thread connection) also areencompassed. The electronic smoking article 200 may be adapted for airintake, which may be provided in a coupler as described, for example, inUS Pat. Pub. No. 2014/0261408 to DePiano et al., the disclosure of whichis incorporated herein by reference in its entirety. The cartridge 204also may include one or more electronic components 250, which mayinclude an IC, a memory component, a sensor, or the like. The electroniccomponent 250 may be adapted to communicate with the control component206 so as to provide an input. See, for example, US Pat. Pub. Nos.2014/0096781 to Sears et al. and 2014/0096782 to Ampolini et al., thedisclosures of which are incorporated herein by reference in theirentirety.

The electronic smoking article can encompass a variety of combinationsof components useful in forming an electronic aerosol delivery device.Reference is made for example to the following: a reservoir and heatersystem for controllable delivery of multiple aerosolizable materialsdisclosed in US Pat. Pub. No. 2014/0000638 to Sebastian et al.;microheaters as disclosed in US Pat. Pub. No. 2014/0060554 to Collett etal.; carbon-based cartridges and components thereof, as disclosed USPat. Pub. No. 2013/0255702 to Griffith, Jr. et al.; single-usecartridges as disclosed in US Pat. Pub. No. 2014/0060555 to Chang etal.; aerosol precursor transport elements, such as disclosed in US Pat.Pub. No. 2014/0209105 to Sears et al.; charging components, such as anadaptor disclosed in US Pat. Pub. No. 2014/0261495 to Novak, III et al.;vibration components, such as disclosed in US Pat. Pub. No. 2015/0020825to Galloway et al.; and batteries, such as disclosed in U.S. Pat. Pub.No. 2010/0028766 to Peckerar et al.

Representative types of aerosol precursor components and formulationsalso are set forth and characterized in U.S. Pat. No. 7,217,320 toRobinson et al. and U.S. Pat. Pub. Nos. 2013/0008457 to Zheng et al.;2013/0213417 to Chong et al.; 2014/0060554 to Collett et al.;2015/0020823 to Lipowicz et al.; and 2015/0020830 to Koller, as well asWO 2014/182736 to Bowen et al, the disclosures of which are incorporatedherein by reference. Other aerosol precursors that may be employedinclude the aerosol precursors that have been incorporated in the VUSE®product by R. J. Reynolds Vapor Company, the BLU™ product by LorillardTechnologies, the MISTIC MENTHOL product by Mistic Ecigs, and the VYPEproduct by CN Creative Ltd. Also desirable are the so-called “smokejuices” for electronic cigarettes that have been available from JohnsonCreek Enterprises LLC.

In certain embodiments, the aerosol precursor comprises a nicotine salt,co-crystal, or salt co-crystal as disclosed herein. In one embodiment,the aerosol precursor composition can comprise, for example, apolyhydric alcohol (e.g., glycerin, propylene glycol, or a combinationthereof), water, a nicotine salt, co-crystal, or salt co-crystal asdescribed herein, and a flavorant (e.g., menthol). Exemplary flavoringagents include vanillin, ethyl vanillin, cream, tea, coffee, fruit(e.g., apple, cherry, strawberry, peach and citrus flavors, includinglime and lemon), maple, menthol, mint, peppermint, spearmint,wintergreen, nutmeg, clove, lavender, cardamom, ginger, honey, anise,sage, cinnamon, sandalwood, jasmine, cascarilla, cocoa, licorice, andflavorings and flavor packages of the type and character traditionallyused for the flavoring of cigarette, cigar, and pipe tobaccos. Syrups,such as high fructose corn syrup, also can be employed. Flavoring agentsalso can include acidic or basic characteristics (e.g., organic acids,such as levulinic acid, succinic acid, and pyruvic acid). Representativetypes of aerosol precursor compositions are set forth in U.S. Pat. No.4,793,365 to Sensabaugh, Jr. et al.; U.S. Pat. No. 5,101,839 to Jakob etal.; U.S. Pat. Pub. No. 2013/0008457 to Zheng et al.; and Chemical andBiological Studies on New Cigarette Prototypes that Heat Instead of BurnTobacco, R. J. Reynolds Tobacco Company Monograph (1988). Thedisclosures of all of the foregoing documents are incorporated herein byreference in their entireties.

One or more acid components can be included within the aerosolprecursor, e.g., to modify the sensory characteristics of the aerosolprecursor and the aerosol produced therefrom. Organic acids particularlymay be incorporated into the aerosol precursor to affect the flavor,sensation, and/or organoleptic properties of nicotine. Such organicacids can be included in the aerosol precursor with nicotine in varyingamounts ranging from greater than equimolar to less than equimolar(based on total organic acid content) with the nicotine. A range oforganic acids can be used in accordance with such embodiments, e.g., asset forth in Perfetti, Beitrage Tabakforschung Int., 12, 43-54 (1983),which is incorporated herein by reference. Certain exemplary organicacids that may be useful include, but are not limited to, such acids astartaric acid, ascorbic acid, fumaric acid, citric acid, malic acid,lactic acid, aspartic acid, salicylic acid, 4-amino salicylic acid,N-acetyl-4-aminosalicylic acid, p-toluenesulfonic acid, succinic acid,pyruvic acid, formic acid, acetic acid, propionic acid, isobutyric acid,butyric acid, alpha-methylbutyric acid, 2-ketobutyric acid, isovalericacid, beta-methylvaleric acid, caproic acid, 2-furoic acid, phenylaceticacid, heptanoic acid, octanoic acid, nonanoic acid, oxalic acid, malonicacid, glycolic acid, levulinic acid, 4-aminobenzoic acid,4-acetamidobenzoic acid, 3-hydroxybenzoic acid, 2,5-dihydroxybenzoicacid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid,3,4-dihydroxybenzoic acid, vanillic acid, mucic acid, cyclamic acid,benzenesulfonic acid, 2-hydroxyethanesulfonic acid,1-hydroxy-2-naphthoic acid, ketoglutaric acid, D-glucuronic acid, maleicacid, glutamic acid, L-pyroglutamic acid, nicotinic acid, isonicotinicacid, gallic acid, phthalic acid, mandelic acid, hippuric acid, cinnamicacid, adipic acid, orotic acid, sorbic acid, clofibric acid, tauricacid, and combinations of two or more such organic acids. By using anicotine salt, co-crystal, or salt co-crystal in place of nicotine, itmay be possible in certain embodiments to reduce and or eliminate theamount of acid advantageously incorporated within the aerosol precursor.

The amount of aerosol precursor composition that is used within thesmoking article is such that the article exhibits acceptable sensory andorganoleptic properties, and desirable performance characteristics. Forexample, it is highly preferred that sufficient aerosol precursorcomposition components, such as glycerin and/or propylene glycol, beemployed in order to provide for the generation of a visible mainstreamaerosol that in many regards resembles the appearance of tobacco smoke.Typically, the amount of aerosol-generating material incorporated intothe smoking article is in the range of about 1.5 g or less, about 1 g orless, or about 0.5 g or less. The amount of aerosol precursorcomposition can be dependent upon factors such as the number of puffsdesired per cartridge used with the smoking article. It is desirable forthe aerosol-generating composition not to introduce significant degreesof unacceptable off-taste, filmy mouth-feel, or an overall sensoryexperience that is significantly different from that of a traditionaltype of cigarette that generates mainstream smoke by burning tobacco cutfiller. The selection of the particular aerosol-generating material andreservoir material, the amounts of those components used, and the typesof tobacco material used, can be altered in order to control the overallchemical composition of the mainstream aerosol produced by the smokingarticle.

Typically, the amount of nicotine incorporated into an aerosol precursorof an electronic smoking article is that amount sufficient to providethe desired amount of free nicotine in the aerosol produced therefrom.For example, the article may provide nicotine in an amount of about 0.01mg to about 0.5 mg, about 0.05 mg to about 1 mg, about 0.08 mg to about0.5 mg, about 0.1 mg to about 0.3 mg, or about 0.15 mg to about 0.25 mgper puff on the article. Accordingly, the amount of nicotine salt,co-crystal, or salt co-crystal incorporated into the aerosol precursorcan be, for example, that amount sufficient to produce these amounts ofnicotine when the article is used.

When the nicotine salts, co-crystals, or salt co-crystals describedherein are used in electronic smoking articles, the temperature at whichnicotine is released into aerosol form from the salt, co-crystal, orsalt co-crystal is an important consideration. It is typically importantthat nicotine is released from the salt, co-crystal, or salt co-crystal(i.e., that the nicotine transfers to aerosol form) at the operatingtemperature of the electronic smoking articles. Although not intended tobe limiting, exemplary operating temperatures of electronic smokingarticles are within the range of about 100° C. to about 500° C. (e.g.,about 120° C. to about 300° C.). Accordingly, selection of anappropriate nicotine salt, co-crystal, or salt co-crystal forincorporation into such products can depend, in part, on thecharacteristics of the bond between the nicotine and the coformer andthe volatility of the salt, co-crystal, or salt co-crystal. For example,nicotine citrate may not be a good salt for an electronic smokingarticle because it is not sufficiently volatile.

Furthermore, in some embodiments, the temperature at which the coformercomponent (or components) is released from a nicotine salt, co-crystal,or salt co-crystal can be a relevant consideration. As it may not beadvantageous for certain coformers (e.g., certain acids) to be presentin the aerosol (and delivered to the user), it can be important toconsider the temperature at which not only the nicotine, but also thecoformer of the nicotine salt, co-crystal, or salt co-crystal transfersto aerosol form. In other embodiments, the coformer(s) of a givennicotine salt, co-crystal, or salt co-crystal may be desirably containedin the aerosol and desirably delivered to the user. In such cases, itmay be advantageous to ensure that such coformer(s) are sufficientlyvolatile at the temperature of use of the electronic smoking article.Additionally, any degradation products produced via heating nicotinesalts, co-crystals, or salt co-crystals to the relevant temperature(i.e., the typical operation temperature of an electronic smokingarticle) should also be evaluated and taken into consideration duringproduct preparation and selection for a particular application. Inparticular, in certain embodiments, acid degradation products producedvia heating nicotine salts, co-crystals, or salt co-crystals to therelevant temperature should be evaluated and taken into consideration.

Accordingly, in certain embodiments, following preparation of thenicotine salts, co-crystals, or salt co-crystals described herein, theyare analyzed to evaluate whether the nicotine and/or coformer and/ordegradation products thereof transfer from the aerosol precursor to theaerosol. Such analysis can be conducted, for example, by highperformance liquid chromatography and/or gas chromatography of thecondensate collected from the aerosol. Both the presence and amount ofnicotine and/or coformer and/or degradation products thereof isevaluated to determine whether a given salt, co-crystal, or saltco-crystal is a good candidate for incorporation within an electronicsmoking article.

In still further embodiments, nicotine salts, co-crystals, and/or saltco-crystals disclosed herein may be incorporated within pharmaceuticalproducts. For example, a nicotine salt, co-crystal, or salt co-crystalcan be used as a replacement for, or in addition to, the nicotine innicotine-containing pharmaceutical products. Such products can be usedfor treatment of a wide variety of conditions, diseases, and disordersresponsive to stimulation of one or more types of nicotinicacetylcholinergic receptors (nAChRs). The products can be used to treatthose types of conditions, diseases, and disorders that have beenreported to be treatable through the use or administration of nicotineas an agonist of nAChRs. As such, the products can be used to treatvarious CNS conditions, diseases, and disorders, and the compositionsalso can be used as smoking cessation aids (i.e., as components of NRT).The combined amount of nicotine present (including nicotine present asthe salt, co-crystal, and/or salt co-crystal form and, optionally, anyone or more other forms of nicotine) is preferably that amount effectiveto treat some symptoms of, or prevent occurrence of the symptoms of, acondition, disease, or disorder from which the subject or patientsuffers. Exemplary conditions, diseases or disorders that can be treatedinclude cognitive disorders such as Alzheimer's disease and attentiondeficit disorder, schizophrenia, Parkinson's disease, Tourette'ssyndrome, ulcerative colitis, dry eye disease, hypertension, depression,overactive bladder, obesity, seven year itch/scabies, and hemorrhoids.Such products may also find use as a treatment to reduce stress or painand/or as a smoking cessation aid.

The shape of the pharmaceutical products can resemble a wide variety ofpill, tablet, lozenge, capsule, caplet, pouch and gum types of productsthat traditionally have been employed for the administration ofpharmaceutical types of products. The general nature of a representativecomposition can be soft or hard to the feel, or of intermediate softnessor hardness; and as such, the composition can be considered to bemalleable, flexible, chewy, resilient, brittle, or the like.Pharmaceutical products containing nicotine salts, co-crystals, or saltco-crystals as provided herein are not limited to oral products, andsuch compositions as creams (including salves, ointments, and pastes),liquids (e.g., sprays or enemas), and the like are also encompassed bythe present invention as well. In addition, the nicotine salts,co-crystals, and salt co-crystals disclosed herein can also beincorporated within various devices for delivery, such as inhalers(e.g., metered dose inhalers, dry powder inhalers, and nebulizers).Pharmaceutical products according to the present invention can contain,in addition to a nicotine salt, co-crystal, and/or salt co-crystal asdescribed herein, one or more pharmaceutically acceptable components,e.g., excipients (e.g., salts, sweeteners, fillers, flavorants,antiadherents, glidants, preservatives and antioxidants, surfactants,dyes or pigments, lubricants, and/or processing aids).

The application as written focuses on the incorporation of novelnicotine salts, co-crystals, and salt co-crystals. However, it is notedthat, in some embodiments, known nicotine salts can be employed incompositions disclosed herein to provide novel compositions and/or novelproducts incorporating such compositions. For example, although notintended to be limiting, known salts such as nicotine L-malate (CAS RN253180-13-1), nicotine 4-acetamidobenzoic acid salt (CAS RN110441-65-1), nicotine 3-hydroxybenzoic acid (CAS RN 1644394-41-1,disclosed, for example, in Int. App. Pub. No. WO2015/006652), nicotine2,5-dihydroxybenzoic acid (CAS RN 6012-21-1), nicotine 4-aminosalicylicacid salt (1-hydroxy-4-amino benzoic acid salt) (CAS RN 20334-41-2),nicotine salicylic acid salt (2-hydroxybenzoic acid salt) (CAS RN29790-52-1), nicotine phthalic acid salt (1,2-benzene dicarboxylic acidsalt) (CAS RN 88660-55-3), nicotine N-acetyl-4-aminosalicylic acid salt(N-acetyl-2-hydroxy-4-aminobenzoic acid salt) (CAS RN 900789-26-6),and/or nicotine di-L-(+)-tartrate dihydrate (CAS RN 6019-06-3) can beused in the compositions and products disclosed herein.

It is further noted that, although the application as written focuses onthe formation of nicotine salts, co-crystals, and salt co-crystals andon the incorporation of such formed nicotine salts, co-crystals, andsalt co-crystals into various products, it may be possible, in someembodiments, to form such nicotine salts, co-crystals, and saltco-crystals in situ. For example, nicotine can be combined with one ormore coformers as broadly described herein, and optionally, othercomponents (e.g., those types of components typically contained in theproduct to be formed), and a nicotine salt, co-crystal, or saltco-crystal is formed in situ. In other words, although it is oftenadvantageous for reasons disclosed herein, isolation and/or purificationof the nicotine salt, co-crystal, or salt co-crystal is not required inall embodiments prior to introduction into a product.

For example, in one embodiment, an aerosol precursor of an electronicsmoking article can be prepared by mixing a nicotine salt, co-crystal,or salt co-crystal with desired aerosol precursor components (e.g.,carriers and flavorants) or can be prepared by mixing nicotine, acoformer (e.g., an acid), and desired aerosol precursor components. See,for example, the methods of incorporating certain salts into aerosoldevices in Int. App. Pub. No. WO2014/182736 to Ploom, Inc., which isincorporated herein by reference.

Aspects of the present invention are more fully illustrated by thefollowing examples, which are set forth to illustrate certain aspects ofthe present invention and are not to be construed as limiting thereof.

EXPERIMENTAL General X-Ray Powder Diffraction (XRPD)

Some X-Ray Powder Diffraction patterns are collected on a Bruker AXS C2GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA), automated XYZstage, laser video microscope for auto-sample positioning and a HiStar2-dimensional area detector. X-ray optics consists of a single Gobelmultilayer mirror coupled with a pinhole collimator of 0.3 mm. A weeklyperformance check is carried out using a certified standard NIST 1976Corundum (flat plate). The beam divergence, i.e., the effective size ofthe X-ray beam on the sample, is approximately 4 mm. A θ-θ continuousscan mode is employed with a sample-detector distance of 20 cm whichgives an effective 20 range of 3.2°-29.7°. Typically the sample isexposed to the X-ray beam for 120 seconds. The software used for datacollection is GADDS for XP/2000 4.1.43 and the data are analyzed andpresented using Diffrac Plus EVA v13.0.0.2 or v15.0.0.0.

Samples run under ambient conditions are prepared as flat platespecimens of powder, without grinding. Approximately 1-2 mg of thesample is lightly pressed on a glass slide to obtain a flat surface.Samples run under non-ambient conditions are mounted on a silicon waferwith heat-conducting compound. The sample is heated to the appropriatetemperature at 20° C./min and subsequently held isothermally for 1minute before data collection was initiated.

Some X-Ray Powder Diffraction patterns are collected on a Bruker D8diffractometer using Cu Kα radiation (40 kV, 40 mA), θ-2θ goniometer,and divergence of V4 and receiving slits, a Ge monochromator and aLynxeye detector. The instrument is performance checked using acertified Corundum standard (NIST 1976). The software used for datacollection was Diffrac Plus XRD Commander v2.6.1 and the data wereanalyzed and presented using Diffrac Plus EVA v15.0.0.0.

Samples are run under ambient conditions as flat plate specimens usingpowder as received. The sample was gently packed into a cavity cut intopolished, zero-background (510) silicon wafer. The sample was rotated inits own plane during analysis. The details of the data collection are:Angular range: 2 to 42° 2θ; Step size: 0.05° 2θ; and collection time:0.5 s/step.

¹H Nuclear Magnetic Resonance CH NMR)

NMR spectra were collected on a Bruker 400 MHz instrument equipped withan auto-sampler and controlled by a DRX400 console. Automatedexperiments were acquired using ICON-NMR v4.0.7 running with Topspinv1.3 using the standard Bruker loaded experiments. For non-routinespectroscopy, data were acquired through the use of Topspin alone.Samples were prepared in DMSO-d₆, unless otherwise stated. Off-lineanalysis was carried out using ACD Spectrus Processor 2012.

Fourier Transform—Infra-Red (FTIR)

Data were collected on a Perkin-Elmer Spectrum One fitted with auniversal Attenuated Total Reflectance (ATR) sampling accessory. Thedata were collected and analyzed using Spectrum v10.0.1 software.

Differential Scanning Calorimetry (DSC)

DSC data were collected on a TA Instruments Q2000 equipped with a 50position auto-sampler. The calibration for thermal capacity was carriedout using sapphire and the calibration for energy and temperature wascarried out using certified indium. Typically 0.5-3 mg of each sample,in a pin-holed aluminum pan, was heated at 10° C./min from 25° C. to300° C. A purge of dry nitrogen at 50 ml/min was maintained over thesample. The instrument control software was Advantage for Q Seriesv2.8.0.394 and Thermal Advantage v5.5.3 and the data were analyzed usingUniversal Analysis v4.5A. Thermo-Gravimetric Analysis (TGA)

TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16position auto-sampler. The instrument was temperature calibrated usingcertified Alumel and Nickel. Typically 5-10 mg of each sample was loadedonto a pre-tared aluminum DSC pan and heated at 10° C./min from ambienttemperature to 350° C. A nitrogen purge at 60 ml/min was maintained overthe sample. The instrument control software was Advantage for Q Seriesv2.5.0.256 and Thermal Advantage v5.5.3 and the data were analyzed usingUniversal Analysis v4.5A.

Polarized Light Microscopy (PLM)

Samples were studied on a Leica LM/DM polarized light microscope with adigital video camera for image capture. A small amount of each samplewas placed on a glass slide, mounted in immersion oil and covered with aglass slip, the individual particles being separated as well aspossible. The sample was viewed with appropriate magnification andpartially polarized light, coupled to a λ false-color filter.

Scanning Electron Microscopy (SEM)

Data were collected on a Phenom Pro Scanning Electron Microscope. Asmall quantity of sample was mounted onto an aluminum stub usingconducting double-sided adhesive tape. A thin layer of gold was appliedusing a sputter coater (20 mA, 120 s).

Water Determination by Karl Fischer Titration (KF)

The water content of each sample was measured on a Metrohm 874 OvenSample Processor at 140° C. or 190° C. with 851 Titrano Coulometer usingHydranal Coulomat AG oven reagent and nitrogen purge. Weighed solidsamples were introduced into a sealed sample vial. Approximately 10 mgof sample was used per titration and duplicate determinations were made.Data collection and analysis using Tiamo v2.2.

Gravimetric Vapor Sorption (GVS)

Sorption isotherms were obtained using a SMS DVS Intrinsic moisturesorption analyzer, controlled by DVS Intrinsic Control software v1.0.1.2(or v 1.0.1.3). The sample temperature was maintained at 25° C. by theinstrument controls. The humidity was controlled by mixing streams ofdry and wet nitrogen, with a total flow rate of 200 ml/min The relativehumidity was measured by a calibrated Rotronic probe (dynamic range of1.0-100% RH), located near the sample. The weight change, (massrelaxation) of the sample as a function of % RH was constantly monitoredby the microbalance (accuracy ±0.005 mg).

Typically 5-20 mg of sample was placed in a tared mesh stainless steelbasket under ambient conditions. The sample was loaded and unloaded at40% RH and 25° C. (typical room conditions). A moisture sorptionisotherm was performed as outlined below (2 scans giving 1 completecycle). The standard isotherm was performed at 25° C. at 10% RHintervals over a 0-90% RH range. Data analysis was carried out usingMicrosoft Excel using DVS Analysis Suite v6.2 (or 6.1 or 6.0).

TABLE 1 Method for SMS DVS Intrinsic experiments Parameter ValueAdsorption - Scan 1 40-90 Desorption/Adsorption - Scan 2 90-0, 0-40Intervals (% RH) 10 Number of Scans 2 Flow rate (ml/min) 200 Temperature(° C.) 25 Stability (° C./min) 0.2 Sorption Time (hours) 6 hour time out

The sample is recovered after completion of the isotherm and re-analyzedby XRPD.

Example 1. Salts of Nicotine with Orotic Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of orotic acid. Orotic acid (50mg+/−1 mg) is weighed into a glass vial and (S)-Nicotine (2 molarequivalents) is dispensed into each vial, vials are stirred at 50° C.for 1 hour, cooled to 5° C. at 0.1° C./min, and stirred at 5° C.overnight. Upon the addition of nicotine, the material was observed tobe a suspension and the material remained a suspension after 1 hour.After cooling, the material was observed to be a pink suspension. Afterstirring at 5° C. overnight, solids are sampled and characterized byXRPD. The XRPD analysis results indicate that the solid present in thevial includes a new crystalline phase form, indicative of the formationof an orotic acid salt.

Various screening experiments are next conducted to evaluate alternative(solvent-based) means for the preparation of orotic salts of nicotine,as the slurrying method in neat nicotine was found to be challenging forrepetition on a larger scale.

Experiments are conducted to evaluate the preparation of an orotic saltvia slow evaporation from various solvents. Orotic acid (50 mg+/−1 mg)is weighed into glass vials and the relevant solvent is added at 3, 10,and 20 volumes at 50° C. to try to form solutions of the orotic acid.Nicotine (1 molar equivalent) is added. The resulting mixtures arestirred at 50° C. for 1 hour, cooled to 5° C. at 0.1° C. per minute, andthen stirred at 5° C. overnight. Solids are sampled and analyzed byXPRD; solids exhibiting new XRPD patterns are filtered and dried undervacuum overnight. See FIGS. 1 and 2.

Samples exhibiting XRPD patterns consistent with the acid/coformer andany samples in the form of oils/gums are matured (shaken in 8 hourcycles at 50° C./RT). Solutions are left to evaporate slowly at ambientconditions via loosened lids. Any resulting solids are sampled andanalyzed by XRPD (see FIG. 3), and ¹H NMR (see FIG. 4) with oils/gumsbeing matured as above. Samples that remain solutions after anti-solventaddition are left to evaporate under ambient conditions. A summary ofthese solvent-mediated screens and the observations associated with eachscreen are provided in Table 2.

TABLE 2 Solvent-mediated screen for formation of salt from nicotine andorotic acid Anti- Solvent solvent Observations THF n/a Undissolved acidafter addition of nicotine Suspension after cooling to 5° C., XPRDindicates crystalline new pattern (“Pattern 1”) Material filtered togive solid Water n/a Solution after addition of nicotine Solution after1 h at 50° C. Solution after cooling to 5° C. Solution after initialevaporating step Gummy solid formed after further evaporation,crystalline new pattern by XRPD. Ethanol Methyl Suspension afteraddition of nicotine tert- Suspension after 1 h at 50° C. butylSuspension after cooling to 5° C., XPRD ether at this stage indicatesnew pattern of weakly (TBME) crystalline material. Suspension aftermaturing for 1 week, XRPD indicates the material is crystalline(“Pattern 1”) MEK n-heptane Suspension after addition of nicotineSuspension after 1 h at 50° C. Suspension after cooling to 5° C., XRPDindicates a new pattern (“Pattern 1” and “Pattern 2” mixture). Materialfiltered to give solid IPA n/a Almost dissolved on addition of nicotine,/water Solution after 1 h at 50° C. (80/20 Solution after cooling to 5°C. volume) Solution after evaporating After further evaporation, XRPD istaken, indicating new pattern (“Pattern 2”). Ethyl n-heptane Undissolvedacid after addition of nicotine acetate Suspension after 1 h at 50° C.,Suspension after cooling to 5° C., XPRD indicates crystalline newpattern (“Pattern 2”) Material filtered to give solid

A further experiment is conducted to evaluate the preparation of anorotic salt via grinding. Orotic acid (50 mg+/−1 mg) is weighed into aglass vial and nicotine (1 molar equivalent) is added, giving a slurry.Two ball bearings (3 mm, stainless steel) are added to the resultingmixture and the sample is ground for 2 hours at 650 rpm in a FritschPulverisette mill, giving a white solid. The material is analyzed byXPRD, indicating a crystalline pattern (“Pattern 2”). The solid isisolated from the grinding vial and triturated with n-heptane to removeexcess nicotine.

In all, two different XRPD patterns were observed for the orotic acidsalts (arbitrarily referred to herein as “Pattern 1” and “Pattern 2,”depending on the method of preparation, as summarized below in Table 3.Table 3 further provides additional characterization data for the oroticacid salts.

TABLE 3 Data correlated to method of preparation of orotic acid saltMethod of XRPD salt Pattern preparation of solid ¹H NMR TGA DSC ResultFormation Pattern 1 Peak shifts, 0.8 wt. % Broad Stable in THF ratioloss 25- endotherm bis salt nicotine:orotic 160° C. onset 120° C. acid1:2.0, 33.4 wt. % Broad trace THF loss 180- endotherm 280° C. onset 138°C. See FIG. 5 Sharp endotherm onset 240° C. See FIG. 5 Formation Pattern1 Peak shifts, 0.6 wt. % Broad Stable in ethanol ratio loss 25-endotherm bis salt nicotine:orotic 180° C. onset 92° C. acid 1:1.9, 34.3wt. % Broad trace EtOH loss 180- endotherm 280° C. onset 127° C. SeeFIG. 6 Broad endotherm onset 190° C. Sharp endotherm onset 239° C. SeeFIG. 6 Neat Pattern 2 Peak shifts, 1.7 wt. % Large broad Stable nicotineratio loss 25- endotherm mono nicotine:orotic 125° C. onset 97° C. saltacid 1:1.3 19.2 wt. % See FIG. 7 loss 125- 230° C. 26.7 wt. % loss 230-280° C. See FIG. 7 Formation Pattern 2 Peak shifts, 1.8 wt. % Largebroad Stable in water ratio loss 25- endotherm mono nicotine:orotic 130°C. onset 106° C. salt acid 1:1.0 22.4 wt. % See FIG. 8 loss 130- 240° C.42.4 wt. % loss 240- 305° C. See FIG. 8 Grinding Pattern 2 Peak shifts,1.8 wt. % Large Stable ratio loss 25- endotherm mono nicotine:orotic125° C. onset 97° C. salt acid 1:1.1 22.6 wt. % Broad loss 125-endotherm 210° C. onset 157° C. 27.1 wt. % See FIG. 9 loss 210- 290° C.See FIG. 9 Formation Pattern 2 Peak shifts, 1.9 wt. % Large broad Stablein IPA ratio loss 25- endotherm mono nicotine:orotic 125° C. onset 106°C. salt acid 1:0.9, 65.2 wt. % See FIG. 10 trace IPA loss 125- 300° C.See FIG. 10 Formation Pattern 2 Peak shifts, 2.5 wt. % Large Stable inethyl ratio loss 25- endotherm mono acetate nicotine:orotic 125° C.onset 105° C. salt acid 1:1.2, 19.1 wt. % Broad trace EtOAc loss 125-endotherm 200° C. onset 138° C. 52.3 wt. % Broad loss 200- endotherm325° C. onset 167° C. See FIG. 11 See FIG. 11 Formation Pattern 1 Peakshifts, 16.8 wt. % Large Stable in MEK and 2 ratio loss 25- endothermmono nicotine:orotic 180° C. onset 98° C. salt acid 1:1.3, 30.6 wt. %Broad trace MEK loss 180- endotherm 280° C. onset 126° C. See FIG. 12See FIG. 12

The orotate salts are prepared on a larger scale. A salt having NicotineOrotate XRPD Pattern 1 (“Orotate Pattern 1”) is prepared by suspendingorotic acid (9.6 g, 0.062 moles) in THF (20 vols, 190 ml) and warmingthe mixture to 50° C. The resulting white suspension is left to stir forca. 30 minutes. After this time, 0.5 equivalents of nicotine (5 ml,0.031 moles) is added and the sample is stirred at 50° C. for 1 hour.The sample is stirred at 50° C. overnight and then cooled to 5° C. at0.2° C./min and stirred at 5° C. for ˜1 hour. A sample is analyzed byXRPD and was found to be consistent with Orotate Pattern 1. The sampleis filtered through a glass frit, washed with THF, sucked dry, and thenfurther dried under vacuum for 3 days at ambient temperature to give afine white powder, 12.47 g=85.3 wt. % yield (“Salt A” in Table 4,below).

A salt having Nicotine Orotate XRPD Pattern 2 (“Orotate Pattern 2”) isprepared by suspending orotic acid (4.8 g, 0.031 moles) in EtOAc (20vols, 100 ml) and warming the mixture to 50° C. The resulting whitesuspension is left to stir for ca. 30 minutes. Nicotine, 1 equivalent (5ml, 0.031 moles), is added and the sample is stirred at 50° C. for 1hour. The sample is cooled to 5° C. at 0.1° C./min and stirred at 5° C.overnight. A sample is analyzed by XRPD and found to be mainlyconsistent with Orotate Pattern 2, although some material exhibitingPattern 1 was present. See FIG. 23. An additional 10 ml (2 equivalents)nicotine is added to push the equilibrium towards the mono-salt, and thesample is left to stir at 5° C. for 3 days. After this time, the sampleis analyzed by XRPD and found to be consistent with Pattern 2. Thesample is filtered through a glass frit, washed with EtOAc, sucked dry,and then further dried under vacuum overnight at ambient temperature togive a fine white powder, 8.43 g=86.0 wt. % yield (“Salt B” in Table 4,below).

The resulting solids are analyzed by various techniques, as summarizedin Table 4, below.

TABLE 4 Characterization Summary of Scaled-up Salts Salt A (prepared inTHF) Salt B (prepared in EtOAc) Appearance Fine white powder Fine whitepowder Yield (dry) 85.3 wt. % 86.0 wt. % XRPD damp Consistent withOrotate Pattern Consistent with Orotate Pattern 2 1 (see FIG. 15) (seeFIG. 23) XRPD dry Orotate Pattern 1 (see FIGS. 15 Orotate Pattern 2 (seeFIGS. 23 and and 16) 24) ¹H NMR Peak shifts, trace THF, 2.0 Peak shifts,trace EtOAc, 1.0 equiv. equiv. acid (see FIG. 17) acid (see FIG. 25)Karl Fischer n/a 2.7 wt. % water (0.5 mol. equiv.) Optical Birefringent,mix of Birefringent, mainly agglomerates microscopy agglomerates andprimary of tiny rounded irregular particles particles, irregular ordiamond with some larger plate shaped shaped plates up to ~30 μm (seeprimary particles, up to ~13 μm FIGS. 19(A) and 19(B)) (see FIGS. 27(A)and 27(B)) SEM Loose agglomerates of plates Rounded porous agglomeratesof and smaller irregular particles tiny particles (see FIGS. 28(A) and(see FIGS. 20(A) and 20(B)) 28(B)) TGA No low temperature weight 2.0 wt.% loss 25-125° C., losses 7.2 wt. % loss 125-180° C., 31.5 wt. % loss190-275° C. 13.5 wt. % loss 180-240° C. 48.3 39.6 wt. % loss 275-320° C.wt. % loss 240-305° C. (see FIG. 21) (see FIG. 29) DSC Sharp endothermonset 239° C. Broad endotherm (2 peaks) onset (111.8 J/g) 102° C. (140.5J/g) (see FIG. 21) Broad endotherm onset 130° C. (23.0 J/g) Sharpendotherm onset 182° C. (6.1 J/g) Sharp endotherm onset 238° C. (62.7J/g) (see FIG. 29) GVS Total weight change 0-90% Total weight change0-90% RH = 0.8 wt. %, steady change in RH = ~60 wt. %, stable until mass80% RH then deliquesced On XRPD of residue showed no desorption,moisture retained change in form down to 60% RH XRPD of residue showedmixture of mainly Orotate Pattern 2 with some Orotate Pattern 1 StaticNo change Subtle changes, mainly Orotate stability (see FIG. 22) Pattern2, sticky material 40° C./75% RH (see FIG. 30) Static Subtle changes,mainly Orotate Sticky after 24 hours, deliquesced stability Pattern 1,runny material after 1 week (see FIG. 30) 25° C./96% RH (see FIG. 22)

Based on the data obtained, Orotate Pattern 1 is understood to be anon-solvated bis-orotate complex. It is not clear how the orotic acid isbound to the nicotine. Although not intending to be limited by theory,it is believed the pKa values make it likely that one of the moleculesof orotic acid is bound to the nicotine as a salt and the other isconnected via hydrogen bonding rather than proton transfer (e.g., in theform of a salt-co-crystal). Specifically, the pKa values of orotic acid(5.85 and 8.95) suggest that in the (S)-nicotine bis-orotate crystallattice, only 1 orotic acid molecule is ionized to form mono-protonated(S)-nicotine (protonation of the pyrrolidine nitrogen) in the salt. Thiswould suggest that the 2^(nd) orotic acid molecule is held in thecrystal lattice by hydrogen bonding rather than by proton transfer andionization (protonation of the pyridine nitrogen in nicotine would notbe predicted). Thus (S)-nicotine bis-orotate may be a salt/co-crystalhybrid form.

This form is thermally stable (melting at 239° C.) and is only slightlyhygroscopic in the GVS experiment. However, longer exposure to highhumidity (25° C./96% RH for 1 week) caused conversion to a runnymaterial. Representative peak listings for the XPRD of nicotine orotate(Pattern 1, i.e., a bis-orotate salt-co-crystal) are provided in Table5.

TABLE 5 Table of peak areas for Nicotine Orotate Pattern 1 RelativeAngle Intensity Intensity Peak 2-Theta ° Count % 1 8.8 5486 95.3 2 9.3244 4.2 3 11.2 134 2.3 4 11.9 193 3.4 5 12.2 126 2.2 6 13.4 1806 31.4 714.2 924 16.1 8 15.6 101 1.8 9 16.5 840 14.6 10 17.7 3721 64.7 11 18.61621 28.2 12 19.0 1420 24.7 13 19.2 269 4.7 14 19.4 311 5.4 15 20.1 2103.6 16 20.7 302 5.3 17 21.3 101 1.8 18 21.8 924 16.1 19 22.5 529 9.2 2022.7 336 5.8 21 23.3 403 7.0 22 24.0 160 2.8 23 24.8 235 4.1 24 25.4 63811.1 25 26.5 5754 100.0 26 27.5 420 7.3 27 27.7 428 7.4 28 28.4 756 13.129 29.3 2277 39.6 30 30.2 143 2.5 31 30.6 143 2.5 32 30.9 176 3.1 3331.6 218 3.8 34 32.0 101 1.8 35 33.5 277 4.8 36 33.9 84 1.5 37 34.3 92.41.6 38 34.9 151 2.6 39 35.6 109 1.9 40 36.4 269 4.7 41 37.3 109 1.9 4237.6 118 2.0 43 38.2 487 8.5 44 39.1 361 6.3

Orotate Pattern 2 is understood to be a mono-salt containing 0.5 moleeq. water, i.e. a mono-orotate hemi-hydrate. The (S)-nicotinemono-orotate hemi-hydrate exhibited complex behavior with an unusual DSCprofile (mp 102° C.—1^(st) onset of a broad endotherm, mp 130° C.—onsetof broad exotherm (recrystallization), 182° C.—small endotherm (anunknown, but reproducible event) and 238° C.—sharp endotherm (mp ofbis-orotate)). Orotate Patterns 1 and 2 have a complex relationship;during crystallization studies, Pattern 1 was observed to precipitateinitially and then convert to Pattern 2 upon stirring at 5° C. or onaddition of an excess of nicotine. Orotate Pattern 2 exhibits complexthermal behavior, so further characterization was carried out. KarlFischer experiments showed that the sample contains 0.5 mole eq. water,which is lost by 140° C. (the first weight loss seen in the TGA). Thesecond weight loss seen in the TGA is not caused by water loss (noadditional water was detected by KF at 190° C.). See FIG. 29.

A variable temperature XRPD experiment showed the conversion of OrotatePattern 2 to Pattern 1 on heating. The first endotherm seen in the DSCis the melt of Pattern 2, with the release of the water and the exothermis the re-crystallization of Pattern 1, with associated loss of nicotine(second weight loss in the TGA). No change was seen in the diffractogramor visually at 180-200° C. so it is not clear what is causing thisendotherm in the DSC (but repeat DSC experiments showed that it isreproducible). The final endotherm and associated weight loss is thedissociation of the mono-salt and release of the remainder of thenicotine to leave orotic acid. This was confirmed by ¹H NMR analysis ofthe residue, which was consistent with orotic acid. Representative peaklistings for the XPRD of nicotine orotate (Pattern 2, i.e., a monoorotate salt) are provided in Table 6, below.

TABLE 6 Table of peak areas for Nicotine Orotate Pattern 2 RelativeAngle Intensity Intensity Peak 2-Theta ° Count % 1 7.7 504 11.3 2 9.12219 49.8 3 9.8 698 15.7 4 11.9 269 6.0 5 12.5 328 7.4 6 13.1 92.5 2.1 714.7 2824 63.4 8 15.4 4455 100.0 9 15.9 311 7.0 10 17.3 4195 94.2 1117.9 462 10.4 12 18.2 1219 27.4 13 18.6 714 16.0 14 19.3 757 17.0 1519.7 933 20.9 16 21.3 378 8.5 17 22.1 353 7.9 18 23.4 580 13.0 19 25.01345 30.2 20 25.4 1875 42.1 21 26.3 925 20.8 22 26.6 328 7.4 23 27.02177 48.9 24 27.8 723 16.2 25 28.7 471 10.6 26 29.2 933 20.9 27 29.51261 28.3 28 30.4 109 2.5 29 31.3 395 8.9 30 32.1 193 4.3 31 33.3 2696.0 32 34.9 210 4.7 33 36.3 160 3.6 34 37.4 429 9.6 35 37.6 168 3.8 3638.5 370 8.3 37 39.2 168 3.8

Orotate Pattern 2 is not stable to exposure to high humidity; after 1week at 40° C./75% RH the sample had become a sticky material (and showssubtle changes in the XRPD diffractogram) whilst after 1 week at 25°C./96% RH the sample had deliquesced. During the GVS experiment thisform did not adsorb much water until 80% RH, where it deliquesced. Onreducing the humidity, the water was lost by 60% RH with analysis of theresidue showing that the sample had re-crystallized. This residue,however, contained some Pattern 1 material, suggesting that some of thenicotine was lost during the deliquescence and re-crystallization of thesalt.

Example 2. Salt of Nicotine with Fumaric Acid

A screening experiment is first conducted to evaluate a solvent freemethod for the formation of a salt of fumaric acid. Orotic acid (50mg+/−1 mg) is weighed into glass vials and (S)-Nicotine (2 molarequivalents) is dispensed into each vial, vials are stirred at 50° C.for 1 hour, cooled to 5° C. at 0.1° C./min, and stirred at 5° C.overnight. Upon the addition of nicotine, the material was observed tobe a suspension and the material remained a suspension (with undissolvedacid) after 1 hour. After cooling, the material was observed to be asolid brown solution. After stirring at 5° C. overnight, solids aresampled and characterized by XRPD. The XRPD analysis results indicatethat the solid present in the vial comprises crystalline material, andpeaks for fumaric acid as well as additional peaks are observed. Thematerial is matured and after 1 week, the material is in the form of abrown oil/white solid. Again, XRPD analysis of this material indicatesthe presence of crystalline material, and peaks for fumaric acid as wellas additional peaks are observed.

Various screening experiments are next conducted to evaluate alternative(solvent-based) means for the preparation of fumaric acid salts ofnicotine. Experiments are conducted to evaluate the preparation offumaric salt via slow evaporation from various solvents. Fumaric acid(50 mg+/−1 mg) is weighed into glass vials and the relevant solvent isadded at 3, 10, and 20 volumes at 50° C. to try to form solutions of thefumaric acid. Nicotine (1 molar equivalent) is added. The resultingmixtures are stirred at 50° C. for 1 hour, cooled to 5° C. at 0.1° C.per minute, and then stirred at 5° C. overnight. Solids are sampled andanalyzed by XPRD (see FIG. 31); solids exhibiting new XRPD patterns arefiltered and dried under vacuum overnight.

Samples exhibiting XRPD patterns consistent with the acid/coformer andany samples in the form of oils/gums are matured (shaken in 8 hourcycles at 50° C./RT). Solutions are left to evaporate slowly at ambientconditions via loosened lids on the vials. Any resulting solids aresampled and analyzed by XRPD (see FIG. 32), with any oils/gums presentat this stage being matured as described above. Samples that remainsolutions after anti-solvent addition are left to evaporate underambient conditions. A summary of these solvent-mediated screens and theobservations associated with each screen are provided in Table 7 below.

TABLE 7 Solvent-mediated screen for formation of salt from nicotine andfumaric acid Anti- Solvent solvent Observations THF n/a Solution afteraddition of nicotine Solution after 1 h at 50° C. Solution after coolingto 5° C. Yellow oil after initial evaporating step Oil matured -remained in oil form No XRPD obtained Water n/a Solution after additionof nicotine Solution after 1 h at 50° C. Solution after cooling to 5° C.Solution after initial evaporating step Oil formed after furtherevaporation No XRPD obtained Ethanol TBME Solution after addition ofnicotine Solution after 1 h at 50° C. Solution after cooling to 5° C.Anti-solvent, TBME added, material remained a solution after addition of600 μL TBME Solution after initial evaporating step Oil formed afterfurther evaporation No XRPD obtained MEK n-heptane Suspension afteraddition of nicotine Suspension after 1 h at 50° C. Viscous oil aftercooling to 5° C. Material matured and remained in oil form No XRPDobtained IPA/ n/a Solution after addition of nicotine water Solutionafter 1 h at 50° C. (80/20 Solution after cooling to 5° C. volume)Solution after initial evaporating step Oil formed after furtherevaporation No XRPD obtained Ethyl n-heptane Partial dissolution afteraddition of nicotine acetate Gummy solid after 1 h at 50° C.,Suspension/gum after cooling to 5° C., XPRD indicates crystallinepattern Material filtered to give solid

A further experiment is conducted to evaluate the preparation of afumaric acid salt via grinding. Fumaric acid (50 mg+/−1 mg) is weighedinto a glass vial and nicotine (1 molar equivalent) is added, giving aslurry. Two ball bearings (3 mm, stainless steel) are added to theresulting mixture and the sample is ground for 2 hours at 650 rpm in aFritsch Pulverisette mill, giving a white paste. The material isanalyzed by XPRD, indicating a new pattern, deliquescing. The solid isisolated from the grinding vial and filtered.

Overall, the neat nicotine screen gave a sticky solid (containing someacid), the grinding screen gave a crystalline solid, and the ethylacetate/heptane screen gave a crystalline solid. Other methods providedan oil or solution. Two different XRPD patterns were observed for thefumaric acid salts (arbitrarily referred to herein as “Fumarate Pattern1” and “Fumarate Pattern 2,” depending on the method of preparation.Fumarate Pattern 1 was made by grinding and by preparation in ethylacetate and is understood to contain 2 equivalents of fumaric acid(non-solvated) and deliquesced at 40° C./75% RH. Fumarate Pattern 2 wasmade in neat nicotine and is understood to be a non-solvated mono salt,and deliquesced at 40° C./75% RH. Table 8 further provides additionalcharacterization data for the fumaric acid salts.

TABLE 8 Data correlated to method of preparation of fumaric acid saltXRPD Pattern of Method of solid salt See FIGS. ¹H NMR preparation 31 and32 See FIG. 33 TGA DSC Result Formation Pattern 2 Peak shifts on 1.0 wt.% loss Broad Deliquesced in neat (damp acid, ratio 25-80° C. endotherm(1 day) nicotine sample), nicotine:orotic Complete wt. onset 25° C.Unstable Pattern 1 acid 1:1.0 loss from See FIG. 34 mono salt (dry ~100°C. sample) See FIG. 34 Grinding Pattern 1 Peak shifts on 4.9 wt. % lossEndotherm Deliquesced acid, ratio 25-90° C. (2 peaks) (1 day)nicotine:fumaric 6.3 wt. % loss onset 74° C. Unstable bis acid 1:1.990-140° C. See FIG. 35 salt (later Complete wt. shown to be loss ~150°C. a mono-salt) See FIG. 35 Formation Pattern 1 Peak shifts on No wt.loss Endotherm Deliquesced in ethyl acid, ratio prior to (2 peaks) (1day) acetate nicotine:fumaric degradation onset 74° C. Unstable saltacid 1:1.5 from ~110° C. See FIG. 36 See FIG. 36

Grinding experiments were carried out at mono- and bis-stoichiometry toconfirm the stoichiometry of Pattern 1 (see FIGS. 37 and 38). Fumaricacid (60 mg) is weighed into vials and 0.5 or 1.0 equivs. Nicotine and 2ball bearings (3 mm, stainless steel) are added. Samples are ground for2 hours at 650 rpm in a Fritsch Pulverisette mill. Samples aretriturated with hexane and dried under vacuum overnight prior tocharacterization. The material prepared with 0.5 equivalents nicotinewas a wet solid after addition of nicotine, and a white solid aftergrinding, giving an XRPD consistent with Fumarate Pattern 1 (as comparedwith material prepared in EtOAc). The material prepared with 1equivalent of nicotine was a paste after adding nicotine, and a whitepaste after grinding, giving an XRPD consistent with Fumarate Pattern 1.As such, results indicate that grinding experiments, carried out atmono- and bis-stoichiometries, both produced solids consistent withFumarate Pattern 1, suggesting that Fumarate Pattern 1 is more likely tobe a mono-salt.

Solvent-mediated experiments are next conducted using a range ofanti-solvents to try to form a more homogeneous powdery solid that iseasier to filter. Experiments are also carried out with 1 moleequivalent of nicotine to confirm the stoichiometry of this form.Fumaric acid (approximately 50 mg) is weighed into 2 ml vials and 1 or 2mole eq. nicotine are added. Samples are left to stir at 50° C. for ˜10minutes and then anti-solvents are added to some of the experiments.Samples were stirred at 50° C. for 1 hour, then were cooled to 5° C. at0.1° C./min. Samples are stirred at 5° C. overnight then filtered, airdried and analyzed by XRPD. Samples are filtered and dried under vacuumovernight prior to re-analysis by XRPD and stoichiometry is determinedby ¹H NMR.

TABLE 9 Preparation of fumaric acid salt in neat nicotine (withanti-solvent) Method of Observation Observation XRPD (dry), salt onaddition after cooling XRPD after filtering/ preparation of solvent to5° C. (damp) evaporation ¹H NMR Neat slurry White solid Fumarate Somechanges, Peak shifts, nicotine (with brown Pattern 2 consistent withratio liquid) material prepared nicotine:fumaric in EtOAc acid 1:1.1Neat gum White solid Fumarate Some changes, Peak shifts, nicotine/(white Pattern 1 consistent with ratio TBME as suspension materialprepared nicotine:fumaric anti-solvent and orange in EtOAc acid 1:1.2sticky layers) Neat gum White solid Fumarate Some changes, Peak shifts,nicotine/ (with white Pattern 1 consistent with ratio heptane assuspension material prepared nicotine:fumaric anti-solvent and orange inEtOAc acid 1:1.4 sticky layers) Neat Gum White solid Fumarate Somechanges, Peak shifts, nicotine/ (with white Pattern 1 consistent withratio hexane as suspension material prepared nicotine:fumaricanti-solvent and orange in EtOAc acid 1:1.2 sticky layers) Neat GumThick Fumarate Fumarate Peak shifts, nicotine/ suspension Pattern 1Pattern 1 ratio THF as nicotine:fumaric anti-solvent acid 1:1.0 NeatNearly Solution n/a n/a nicotine/ dissolved dichloromethane (DCM) asanti-solvent Neat Gum White solid Fumarate Fumarate Peak shifts,nicotine/ (with white Pattern 1 Pattern 1 ratio EtOAc as suspensionnicotine:fumaric anti-solvent and orange acid 1:1.1 sticky layers) NeatGum Thick Fumarate Fumarate Peak shifts, nicotine/ suspension Pattern 1Pattern 1 ratio MEK as nicotine:fumaric anti-solvent acid 1:1.0 Neat GumSolution n/a n/a nicotine/ IPA as anti-solvent

Results show that Fumarate Pattern 1 was made from all of theexperiments presented in Table 9 where an anti-solvent was used andwhere a solid was formed. It was determined that experiments using THFand MEK are preferred methods for producing Fumarate Pattern 1. It wasonly possible to make Fumarate Pattern 2 from neat nicotine, whichresulted in sticky solids, which proved difficult to filter. Once dried,the Pattern 2 solids had converted to Pattern 1. Further analysis of theoriginal Fumarate Pattern 2 sample, showed that this sample alsoconverted to Fumarate Pattern 1 on drying.

Characterization results indicate that Fumarate Pattern 1 is a mono-saltand not a bis-salt as was previously thought. When using anti-solvent towash away excess nicotine and to form a material amenable to filtration,Pattern 2 converts to Pattern 1, an observation consistent with thesetwo forms being polymorphs of a mono-salt. Fumarate Pattern 2 is formedin neat nicotine, forming a very hard gum that is not practical toisolate on a large scale. Pattern 2 samples that were filtered from neatnicotine and dried in a vacuum oven converted to a form similar toFumarate Pattern 1 on drying. Although not intending to be limited bytheory, it is believed that Fumarate Pattern 2 represents a metastablepolymorph of the mono-fumarate salt.

The fumarate salts are prepared on a larger scale. Fumaric acid (3.6 g,0.031 moles) is added to nicotine (2 mole equivalents, 10 ml) and warmedto 50° C. The sample is stirred at 50° C. for 30 minutes, causingpartial dissolution of the acid. THF (10 vols with respect to the acid,40 ml) is added, forming a gummy precipitate and the sample is stirredat 50° C. for 1 hour. The sample is then cooled to 5° C. at 0.1° C./minand stirred at 5° C. overnight. A sample of the resulting whitesuspension is analyzed by XRPD and found to be consistent with FumaratePattern 1 (see FIG. 39). The sample is filtered through a glass frit,washed with THF, sucked dry and then further dried under vacuum for 3days at ambient temperature to give a sticky, coarse, off-white powder,4.68 g=54.6 wt. % yield.

The resulting solid is analyzed by various techniques, as summarizedbelow in Table 10.

TABLE 10 Characterization Summary of Scaled-up Fumarate Salt Fumaratesalt (prepared in THF) Appearance Sticky, coarse white powder Yield(dry) 54.6 wt. % XRPD damp Fumarate Pattern 1 See FIG. 39 XRPD dryFumarate Pattern 1 See FIG. 39 ₁H NMR Peak shifts, no THF, 1.0 equiv.acid Karl Fischer n/a Optical Large agglomerates of particles,microscopy sticky material, not possible to disperse in oil See FIGS.40(A) and 40(B) SEM Loose agglomerates of particles with a poroussurface with cracks and indentations See FIGS. 41(A) and 41(B) TGA Nolow temperature weight losses Gross degradation after ~120° C. See FIG.42 DSC Sharp endotherm onset 89° C. (123.0 J/g) See FIG. 42 GVS Totalweight change 0-90% RH = 82 wt. %, sample deliquesces and remains aliquid Sample does not reach equilibrium on adsorption steps Nohysteresis on desorption Static stability Deliquesced after 24 hours 40°C./75% RH Static stability Deliquesced after 24 hours 25° C./96% RH

Representative peak listings for the XPRD of nicotine fumarate (Pattern1, i.e., a non-solvated mono fumarate salt) are provided in Table 11,below.

TABLE 11 Table of peak areas for nicotine fumarate Relative AngleIntensity Intensity Peak 2-Theta ° Count % 1 11.6 148 3.7 2 11.8 49112.4 3 12.2 337 8.5 4 13.8 189 4.8 5 14.1 621 15.7 6 14.4 189 4.8 7 14.92696 68.4 8 16.1 177 4.5 9 16.5 189 4.8 10 16.9 154 3.9 11 17.3 573 14.512 17.5 1395 35.4 13 18.0 76.9 1.9 14 18.4 3943 100.0 15 18.8 402 10.216 19.9 3175 80.5 17 20.2 514 13.0 18 20.8 845 21.4 19 21.5 160 4.0 2022.0 296 7.5 21 22.4 3571 90.6 22 22.6 1507 38.2 23 23.2 290 7.3 24 23.51697 43.0 25 24.2 981 24.9 26 24.4 1413 35.8 27 24.7 189 4.8 28 25.2 57914.7 29 25.8 1052 26.7 30 26.6 526 13.3 31 27.1 154 3.9 32 27.7 508 12.933 28.1 396 10.0 34 28.6 786 19.9 35 29.2 88.7 2.2 36 29.8 502 12.7 3730.2 231 5.8 38 30.8 94.6 2.4 39 31.0 118 3.0 40 31.4 378 9.6 41 32.1384 9.7 42 33.2 231 5.8 43 34.3 118 3.0 44 34.6 136 3.4 45 35.4 100 2.546 35.8 142 3.6 47 36.6 88.7 2.2 48 38.9 118 3.0 49 39.6 100 2.5 50 40.0106 2.7 51 40.7 148 3.7 52 41.6 213 5.4

Fumarate Pattern 1 is understood to be a non-solvated mono-salt, whichis prone to deliquescing at elevated humidity. This form is hygroscopicand needs to be protected from moisture as it is shown to constantlygain moisture from 0-90% RH (82% weight gain) in the GVS isotherm anddeliquesces at elevated humidities (>75% RH). Further, once itdeliquesces, it does not re-crystallize when the humidity is reduced.

Example 3. Salts of Nicotine with L-Pyroglutamic Acid

Under most conditions studied (comparable to those described above withrespect to attempts to prepare salts from nicotine and orotic acid andfumaric acid), mixtures of L-pyroglutamic acid and nicotine yielded oilsor gums. However, in neat nicotine, some crystalline material isobtained.

Pyroglutamic acid (50 mg+/−1 mg) is weighed into a glass vial and(S)-Nicotine (2 molar equivalents) is dispensed into the vial, the vialis stirred at 50° C. for 1 hour, cooled to 5° C. at 0.1° C./min, andstirred at 5° C. overnight. Upon the addition of nicotine, the materialwas observed to be a suspension and the material remained a suspension(with undissolved acid) after 1 hour. After cooling, the material wasobserved to be a white solid. After stirring at 5° C. overnight, solidsare sampled and characterized by XRPD. The XRPD analysis resultsindicate that the solid present in the vial is partially crystalline.This material was identified as a possible salt, but was verysticky/hygroscopic after drying. The material was determined to have anicotine:acid ratio of 1:˜4.5 and excess nicotine could not be washedaway with n-heptane. The material deliquesced at ambient conditions.Attempts to mature the material resulted in the formation of a brownoil, which was not further analyzed.

Example 4. Pyrolysis Studies

The salts of Examples 1 and 2 (nicotine mono-fumarate, nicotinemono-orotate hemi-hydrate, and nicotine bis-orotate) decompose whenexposed to 650° C., liberating mostly nicotine (97% peak areas).

Many modifications and other embodiments of the invention will come tomind to one skilled in the art to which this invention pertains havingthe benefit of the teachings presented in the foregoing description.Therefore, it is to be understood that the invention is not to belimited to the specific embodiments disclosed and that modifications andother embodiments are intended to be included within the scope of theappended claims. Although specific terms are employed herein, they areused in a generic and descriptive sense only and not for purposes oflimitation.

What is claimed:
 1. A salt or salt-co-crystal of nicotine and oroticacid.
 2. The salt or salt-co-crystal of claim 1, wherein thesalt-co-crystal is a bis-orotic acid salt-co-crystal.
 3. The salt orsalt-co-crystal of claim 2, wherein the bis-orotic acid salt-co-crystalis in hemihydrate form.
 4. The salt or salt-co-crystal of claim 1,wherein the salt is a mono-orotic acid salt.
 5. The salt orsalt-co-crystal of claim 1, wherein at least about 50% of the salt orsalt-co-crystal is in crystalline form.
 6. The salt or salt-co-crystalof claim 1, characterized by an X-ray powder diffraction pattern havingpeaks at one or more of the following 2-theta diffraction angles: 8.8,13.4, 17.7, 26.5, and 29.3.
 7. The salt or salt-co-crystal of claim 1,characterized by an X-ray powder diffraction pattern having peaks at oneor more of the following 2-theta diffraction angles: 9.1, 14.7, 15.4,17.3, 25.0, 25.4, and 27.0.
 8. An electronic smoking article comprisingan inhalable substance medium contained within a cartridge body and aheating member positioned to provide heat to at least a portion of theinhalable substance medium, wherein the inhalable substance mediumcomprises nicotine fumarate or the salt or salt-co-crystal of nicotineand orotic acid of claim
 1. 9. The electronic smoking article of claim8, wherein the inhalable substance medium further comprises one or moreof glycerin, water, and a flavorant.
 10. The electronic smoking articleof claim 8, wherein the amount of nicotine fumarate or salt orsalt-co-crystal of nicotine and orotic acid is that amount sufficient toprovide nicotine in an amount of about 0.01 mg to about 0.5 mg per puffon the article.
 11. The electronic smoking article of claim 8, whereinthe amount of nicotine fumarate or salt or salt-co-crystal of nicotineand orotic acid is that amount sufficient to provide nicotine in anamount of about 0.05 mg to about 0.3 mg per puff on the article.
 12. Theelectronic smoking article of claim 8, wherein the amount of nicotinefumarate or salt or salt-co-crystal of nicotine and orotic acid is thatamount sufficient to provide nicotine in an amount of about 0.1 mg toabout 0.2 mg per puff on the article.
 13. A smokeless tobacco productcomprising nicotine fumarate or the salt or salt-co-crystal of nicotineand orotic acid of claim
 1. 14. The smokeless tobacco product of claim13, selected from the group consisting of loose moist snuff (e.g.,snus); loose dry snuff; chewing tobacco; pelletized tobacco pieces;extruded or formed tobacco strips, pieces, rods, cylinders or sticks;finely divided ground powders; finely divided or milled agglomerates ofpowdered pieces and components; flake-like pieces; molded tobaccopieces; gums; rolls of tape-like films; readily water-dissolvable orwater-dispersible films or strips; meltable compositions; lozenges;pastilles; and capsule-like materials possessing an outer shell and aninner region.
 15. A pharmaceutical product comprising nicotine fumarateor the salt or salt-co-crystal of nicotine and orotic acid of claim 1.16. The pharmaceutical product of claim 15, in a form selected from thegroup consisting of a pill, tablet, lozenge, capsule, caplet, pouch,gum, inhaler, solution, and cream.
 17. A lozenge comprising nicotinefumarate or the salt or salt-co-crystal of nicotine and orotic acid ofclaim 1 and at least about 50% by weight isomalt.
 18. A method ofpreparing a salt or salt-co-crystal of nicotine and orotic acid,comprising combining nicotine and orotic acid to form a solid andisolating the solid.
 19. The method of claim 18, wherein the combiningcomprises grinding the nicotine and orotic acid or comprises mixing thenicotine and orotic acid in neat nicotine or in a solvent selected fromthe group consisting of water, MEK, IPA, ethyl acetate and mixturesthereof, and wherein the solid is a mono-orotate salt hemihydrate. 20.The method of claim 18, wherein the combining comprises mixing thenicotine and orotic acid in THF, ethanol, or a mixture thereof, andwherein the solid is a non-solvated, bis-orotate salt-co-crystal.